Fused bicyclic compounds for the treatment of disease

ABSTRACT

Described herein are fused bicyclic compounds, compositions, and methods for their use for the treatment of disease.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.15/630,189, filed Jun. 22, 2017, which is a continuation ofInternational Patent Application No. PCT/IB2015/002549, filed Dec. 21,2015, which claims the benefit of U.S. provisional application Ser. No.62/095,646, filed Dec. 22, 2014, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

Farnesoid X receptor (FXR) is a member of the nuclear hormone receptorsuperfamily of ligand-activated transcription factors. Bile acids areFXR physiological ligands. On activation by bile acids, FXR regulates awide variety of target genes that are critically involved in the controlof bile acid, lipid and glucose homeostasis. Thus, FXR plays a key rolein the pathogenesis of cholestatic diseases, non-alcoholic fatty liverdisease and inflammatory bowel disease.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), pharmaceuticalcompositions that include such compounds, and methods of use thereof,for modulating FXR. In one aspect is the administration of at least oneFXR modulator described herein to a mammal in the treatment of diseases,disorders or conditions that would benefit from FXR modulation.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted, aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or    -   R²⁷ and R²⁸ together with the nitrogen atom to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ib), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ic), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Id), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ie), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (If), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ig), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ih), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ii), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ij), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein n is 0. In a further embodiment isa compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R⁶ and R⁷ are hydrogen. In a further embodimentis a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R⁴ and R⁵ are C₁-C₆alkyl. In a furtherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein R⁴ and R⁵ are methyl. In a furtherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein R³ is —C(O)N(R²¹)R²². In a furtherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein R³ is —C(O)N(R²¹)R²² and R²¹ ishydrogen and R²² is optionally substituted aryl. In another embodimentis a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R³ is —C(O)R²⁰. In another embodiment is acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), or (Ij), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R³ is —C(O)R²⁰ and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR³ is —S(O)₂R²⁰. In another embodiment is a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR³ is —S(O)₂R²⁰ and R²⁰ is optionally substituted aryl.

In another aspect provided herein is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or    -   R²⁷ and R²⁸ together with the nitrogen atom to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring;

R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIa), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIb), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIc), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IId), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIe), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIf), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIg), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIh), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIi), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIj), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), (IIi), or (IIj), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein n is 0. In anotherembodiment is a compound of Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), or (IIj), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein n is 1 and R¹¹ is selectedfrom the group consisting of halogen, C₁-C₆alkyl, and C₁-C₆alkoxy. Inanother embodiment is a compound of Formula (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), (IIi), or (IIj), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein n is 1 and R¹¹ ishalogen. In another embodiment is a compound of Formula (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), or (IIj), or apharmaceutically acceptable salt, solvate, or prodrug thereof, wherein nis 1 and R¹¹ is C₁-C₆alkyl. In another embodiment is a compound ofFormula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),or (IIj), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein n is 1 and R¹¹ is C₁-C₆alkoxy. In another embodiment isa compound of Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), or (IIj), or a pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein n is 2 and each R¹¹ is independentlyselected from the group consisting of halogen, C₁-C₆alkyl, andC₁-C₆alkoxy.

In another aspect, provided herein is a compound having the structure ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring;    -   each R¹⁵ is independently selected from the group consisting of        halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl, —C(O)OR¹², —C(O)N(R¹³)R¹⁴, —OC(O)OR¹²,        —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and —N(R¹³)C(O)N(R¹³)R¹⁴;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   n is 0, 1, 2, or 3    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In another aspect, provided herein is a compound having the structure ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring;    -   each R¹⁵ is independently selected from the group consisting of        halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl, —C(O)OR¹², —C(O)N(R¹³)R¹⁴, —OC(O)OR¹²,        —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and —N(R¹³)C(O)N(R¹³)R¹⁴;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   n is 0, 1, 2, or 3    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In one embodiment is a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, wherein nis 0. In another embodiment is a compound of Formula (III) or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, wherein nis 1 and R¹⁵ is selected from the group consisting of halogen,C₁-C₆alkyl, and C₁-C₆alkoxy. In another embodiment is a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein n is 1 and R¹⁵ is halogen. In anotherembodiment is a compound of Formula (III) or (IV), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein n is 1 and R¹⁵ isC₁-C₆alkyl. In another embodiment is a compound of Formula (III) or(IV), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein n is 1 and R¹⁵ is C₁-C₆alkoxy. In another embodiment isa compound of Formula (III) or (IV), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein n is 2 and each R¹⁵ isindependently selected from the group consisting of halogen, C₁-C₆alkyl,and C₁-C₆alkoxy.

In another embodiment is a compound of Formula (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV),or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein R³⁰ is F. In a further embodiment is a compound of Formula (II),(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj),(III), or (IV), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R³⁰ is

In a further embodiment is a compound of Formula (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV),or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein R³⁰ is

In a further embodiment is a compound of Formula (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV),or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein p is 1. In a further embodiment is a compound of Formula (II),(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj),(III), or (IV), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R³¹ is halogen. In a further embodiment is acompound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf),(IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein R³¹ is F. In afurther embodiment is a compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR⁶ and R⁷ are hydrogen. In a further embodiment is a compound of Formula(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV), or a pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein R⁴ and R⁵ are C₁-C₆alkyl. In a furtherembodiment is a compound of Formula (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR⁴ and R⁵ are methyl.

In another embodiment is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR² is —C(O)OR²⁵. In a further embodiment is a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R² is —C(O)OR²⁵ and R²⁵ is C₁-C₆alkyl. In a furtherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein R² is —C(O)OR²⁵and R²⁵ is methyl. In another embodiment is a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R² is —C(O)OR²⁵ and R²⁵ is ethyl. In another embodimentis a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein R² is —C(O)OR²⁵ and R²⁵ isisopropyl. In another embodiment is a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment is acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein R² is —C(O)N(R²⁵)R²⁶ and R²⁵is C₁-C₆alkyl. In a further embodiment is a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R² is —C(O)N(R²⁵)R²⁶ and R²⁵ is methyl. In anotherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein R² is—C(O)N(R²⁵)R²⁶ and R²⁵ is ethyl. In another embodiment is a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV), or a pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein R² is —C(O)N(R²⁵)R²⁶ and R²⁵ is isopropyl.In another embodiment is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR² is —C(O)N(R²⁵)R²⁶ and R²⁶ is hydrogen. In a further embodiment is acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein R¹ is hydrogen. In a furtherembodiment is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, wherein R⁸ is hydrogen.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablediluent, excipient or binder. In one embodiment, the pharmaceuticalcomposition comprising the compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, is formulated for aroute of administration selected from oral administration, parenteraladministration, buccal administration, nasal administration, topicaladministration, or rectal administration.

In another aspect is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof; wherein thedisease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis or obesity. In anotherembodiment is the use of a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV) in themanufacture of a medicament for the treatment of a disease, disorder, orcondition that would benefit from FXR modulation. In another embodimentis the use of a FXR modulator in the manufacture of a medicament for usein the treatment of a disease, disorder or condition in a mammal,wherein the disease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis or obesity.

In another aspect is a method of modulating FXR activity comprisingcontacting FXR, or portion thereof, with a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The Farnesoid X receptor (FXR; also referred to as NR1H4; nuclearreceptor nomenclature committee 1999) is a member of the steroid andthyroid hormone nuclear receptor superfamily of ligand regulatedtranscription factors. FXR is highly expressed in the liver, kidney,intestines and the adrenals and at lower levels in the vasculature(Forman et al., Cell 1995, 81(5):687-93). Bile acids, the end-productsof cholesterol catabolism, bind directly to the ligand binding pocket ofFXR and act as agonists to increase the receptor's ability to activatetranscription (Makishima et al., Science 1999, 284(5418):1362-5 1999; Miet al., Mol Cell 2003, 11(4):1093-100; Parks et al., Science 1999,284(5418):1365-8; Wang et al., Mol Cell 1999, 3(5):543-53). In responseto bile acid binding FXR regulates a network of genes that control thesynthesis, transport, and catabolism of bile acids, but alsotriglycerides and cholesterol (Chawla et al., Cell 2000, 103(1):1-4;Repa and Mangelsdorf, Annu Rev Cell Dev Biol 2000, 16:459-81). Thus FXRfunctions as a regulator of lipid metabolism by modifying geneexpression in response to quantitative changes in the metabolism andbreakdown of cholesterol. In support of this conclusion, studies inhumans and in animals have demonstrated that modifying bile acid levelscan have profound effects on plasma triglyceride and cholesterol levels(Angelin et al., J Lipid Res 1978, 19(8): 1017-24; Bateson et al., Br JClin Pharmacol 1978, 5(3):249-54; Iser and Sali, Drugs 1981,21(2):90-119; Kuroki et al., Lipids 1999, 34(8):817-23).

Metabolic disease including obesity, diabetes, hypertension, andcardiovascular disease, are diseases driven by both mulitfactorialgenetics (thrifty genotypes) as well as lifestyle habits, and are nowreaching epidemic proportions in developed nations. It is believed thatincreasingly high caloric diets combined with sedentary life styles aremajor contributors to the growing incidence of these diseases.Importantly hyperlipidemia is associated with many types of metabolicdisease, and statistics from the American Heart Association indicatethat approximately half of the adult population in the United States hasplasma cholesterol levels that put individuals at risk for thedevelopment of cardiovascular disease (American Heart Association, Heartdisease and stroke statistics—2005 update; 2005:1-59). Furthermore, theThird Report of the National Cholesterol Education Program Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III; ATPIII, National CholesterolEducation Program 2001) has identified elevated triglyceride levels asan independent risk factor for the development of cardiovasculardisease. Approximately one third of the adult population in the UnitedStates that have elevated cholesterol levels also have increasedtriglycerides. The elevation in plasma triglycerides has now beenrecognized as an early and dominant dyslipidemic symptom in patientswith obesity, metabolic syndrome and diabetes and has been suggested toplay a causative role in the development of insulin resistance and typeII diabetes (Hegarty et al., Acta Physiol Scand 2003; 178(4):373-83;Shulman, J Clin Invest 2000; 106(2):171-6).

Current standard of care for hyperlipidemia focuses on lowering lowdensity lipoprotein cholesterol (LDL) using the statin class ofhydroxymethyl-glutaryl-CoA reductase inhibitors (National CholesterolEducation Program 2001). However, even after statin therapy asignificant number of patients still exhibit elevated levels of plasmatriglycerides and triglyceride-rich lipoproteins including very lowdensity lipoproteins (VLDL) and intermediate density lipoproteins (IDL)(Friday, Exp Biol Med (Maywood) 2003, 228(7):769-78; Quilliam et al., JManag Care Pharm 2004, 10(3):244-50). To treat this population ofpatients with concurrent high plasma triglyceride levels the ATPIII hasidentified lowering of triglyceride-rich cholesterol fractions(VLDL+IDL) as a secondary target of drug therapy (National CholesterolEducation Program 2001). Unfortunately treatment of such patients withfibrates, an approved class of triglyceride lowering drugs, haspotential adverse side effects, including the possibility of increasedLDL cholesterol as well as carrying the risk of fatal rhabdomyolysis, sothat combination therapy must proceed cautiously (National CholesterolEducation Program 2001). Similarly nicotinic acid, a second approvedtriglyceride lowering agent, is contraindicated in patients with insulinresistance and type II diabetes (Capuzzi et al., Curr Atheroscler Rep2000, 2(1):64-71). Taken together these observations highlight the needfor an effective therapeutic agent for the lowering of triglycerides andnon-HDL cholesterol in patients with cardiovascular disease, diabetes,and metabolic syndrome.

The maintenance of lipid homeostasis requires coordinate control ofcholesterol and triglyceride synthesis, transport, up-take, andexcretion. Interestingly, studies in human and in animal models haveuncovered a link between bile acids, the metabolic end-product ofcholesterol metabolism, and lipid homeostasis. Clinical studies in thelate 1970s exploring the effect of bile acids on cholesterol gallstonesdemonstrated that treatment with chenodeoxycholic acid (CDCA) reducesplasma triglyceride levels (Bateson et al., Br J Clin Pharmacol 1978,5(3):249-54; Iser and Sali, Drugs 1981, 21(2):90-119). In contrast,treatment with bile acid sequestrants, which deplete intestinal bileacids, increase triglycerides (Angelin et al., J Lipid Res 1978;19(8):1017-24). Importantly the bile acid-dependent decrease intriglycerides is mediated, at least in part, through a reduction in theproduction of VLDL (Hirokane et al., J Biol Chem 2004, 279(44):45685-92;Post et al., Arterioscler Thromb Vasc Biol 2004, 24(4):768-74; Sirventet al., FEBS Lett 2004, 566(1-3): 173-7; Kang and Davis, Biochim BiophysActa 2000, 1529(1-3):223-30). While bile acids are known to mediate theabsorption of cholesterol and fat in the intestine the mechanistic basisfor the connection between bile acids and lipid levels remained unclearuntil the recent characterization of FXR.

The FXR was originally cloned and classified as an orphan member of thenuclear hormone receptor superfamily based upon DNA sequence homology.Initial studies identified farnesol as a ligand for FXR (Forman et al.,Cell 1995, 81(5):687-93), however, subsequent analysis demonstrated thatbile acids bind directly to the ligand binding domain of FXR andfunction as activators of the receptor's transcriptional activity. Thebinding affinities of bile acids for FXR is near the concentration thatthese compounds reach in animals (μM) lending support to the idea thatbile acids function as endogenous ligands in vivo (Makishima et al.,Science 1999, 284(5418):1362-5 1999; Mi et al., Mol Cell 2003,11(4):1093-100; Parks et al., Science 1999, 284(5418):1365-8; Wang etal., Mol Cell 1999, 3(5):543-53). Activation of FXR upon bile acidbinding leads to transcriptional down-regulation of cholesterol7α-hydroxylase (CYP7A1), the rate limiting enzyme in the conversion ofcholesterol to bile acids. Inhibition of CYP7A1 by bile acids occurs viaFXR-dependent induction of the small heterodimeric partner (SHP; alsoreferred to as NR0B2, Nuclear Receptor Nomenclature Committee 1999), atranscriptional repressor. Binding sites for FXR have been identified inthe SHP promoter indicating that this gene is a direct target of FXR (Luet al., Mol Cell 2000, 6(3):507-15; Goodwin et al., Mol Cell 2000,6(3):517-26). Thus bile acid-dependent repression of CYP7A1 is indirectand results from a transcriptional cascade initiated by FXR. A similarSHP-dependent mechanism has been described for the bile acid repressionof another gene involved in bile acid synthesis, CYP8B1 (sterol 12ahydroxylase; Yang et al., Biochim Biophys Acta 2002, 1583(1):63-73), andfor the sodium/taurocholate cotransporter peptide (NTCP) which is one oftwo major transporters responsible for bile acid up-take by the liver(Denson et al., Gastroenterology 2001; 121(1):140-7). In contrast thegenes encoding the bile salt export pump (BSEP) and the multidrugresistance protein 2 (MDR2) are directly induced by FXR, once again viabinding sites in their respective promoter regions (Ananthanarayanan etal., J Biol Chem 2001, 276(31):28857-65; Huang et al., J Biol Chem 2003,278(51):51085-90; Liu et al., J Clin Invest 2003, 112(11):1678-87).These two transporters are required for the transfer of bile acids(BSEP) and phospholipids (MDR2) out of the hepatocytes into the biliarysystem. This pattern of FXR-dependent gene expression defines a classicfeedback loop where high levels of bile acids inhibit new bile acidsynthesis and bile acid uptake while simultaneously promoting their ownclearance.

The regulation of bile acid synthesis and transport by FXR has importantimplications for cholesterol metabolism. Repression of CYP7A1 and CYP8B1impacts the bile acid synthetic pathway at two important points. First,inhibition of CYP7A1, the rate limiting enzyme, can decrease synthesisand reduce the size of the bile acid pool. Second, inhibition of CYP8B1alters bile acid composition by favoring the production of morehydrophilic bile acids such as CDCA (muricholic acid/MCA in mice)(Russell, Annu Rev Biochem 2003, 72:137-74). Importantly, studies inmice have demonstrated that the more hydrophilic bile acids are lessefficient at promoting intestinal cholesterol absorption (Wang et al.,Am J Physiol Gastrointest Liver Physiol 2003, 285(3):G494-502).

Although regulating bile acid synthesis may contribute to theFXR-dependent effects on lipid metabolism, gene expression analysisindicates that FXR also directly influences triglyceride synthesis andVLDL production. FXR agonists induce the genes encoding fibroblastgrowth factor 19 (Holt et al., Genes Dev 2003, 17(13):1581-91),acylation stimulating protein (a proteolytic product of complement C3;Li et al., J Biol Chem 2005, 280(9):7427-34), apolipoprotein CII (Kastet al., Mol Endocrinol 2001, 15(10): 1720-8), and apolipoprotein AV(Prieur et al., J Biol Chem 2003, 278(28):25468-80) all of which areknown to promote the clearance and oxidation of fat carried bytriglyceride rich lipoproteins. Additionally FXR inhibits expression ofthe genes encoding apolipoprotein CIII (Claudel et al., Gastroenterology2003, 125(2):544-55), an inhibitor of lipoprotein lipase, and the sterolresponse element binding protein Ic (SREBP1c; Watanabe et al., J ClinInvest 2004, 113(10):1408-18). SREBP1c, a member of basichelix-loop-helix family of transcription factors, functions as a mastertranscriptional regulator of the enzymes required for fatty acidsynthesis (Osborne, J Biol Chem 2000, 275(42):32379-82). Taken togetherthe genetic network controlled by FXR defines a signal transductionsystem poised to respond to changes in fat and carbohydrate dietaryintake-driven lipid homeostasis. High levels of cholesterol in the liverwill lead to increased production of bile acids and subsequentactivation of FXR. In response to this activating signal FXR decreasesthe absorption of cholesterol in the intestine, favoring excretion,increases the clearance and oxidation of triglycerides and decreases thesynthesis of fatty acids leading to a reduction in VLDL production.

The ability of FXR to regulate bile-acid synthesis, clearance andhomeostasis as supported by the ability of FXR ligands to promote thetransport of bile acid and phospholipids out of the liver suggests autility for such compounds in diseases of disturbed bile acid andcholesterol flow such as Primary Biliary cirrhosis and NASH. In thisregard FXR agonists have been shown to be effective in animal models ofcholestasis, gallstones, and liver fibrosis (Liu et al., J Clin Invest2003, 112(11):1678-87; Fiorocci et al., Gastroenterology 2004,127(5):1497-512; Fiorocci et al., J Pharmacol Exp Ther 2005,313(2):604-12; Fiorocci et al., J Pharmacol Exp Ther 2005,314(2):584-95).

In some embodiments, compounds disclosed herein are used in thetreatment of a disease, disorder or condition in a mammal that wouldbenefit from FXR modulation.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, is a method oftreating a disease, disorder or condition in a mammal that would benefitfrom FXR modulation comprising administering a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is selected fromnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis and obesity. In some embodiments, is a method of treating adisease, disorder or condition in a mammal that would benefit from FXRmodulation comprising administering a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH). In some embodiments, is a method of treating adisease, disorder or condition in a mammal that would benefit from FXRmodulation comprising administering a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is hyperlipidemia. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder orcondition in a mammal is hypercholesterolemia.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder orcondition in a mammal is hypertriglyceridemia. In some embodiments, is amethod of treating a disease, disorder or condition in a mammal thatwould benefit from FXR modulation comprising administering a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder or condition in a mammal isdyslipidemia. In some embodiments, is a method of treating a disease,disorder or condition in a mammal that would benefit from FXR modulationcomprising administering a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is lipodystrophy. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising administeringa compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt or solvate thereof, wherein the disease, disorder or condition in amammal is atherosclerosis. In some embodiments, is a method of treatinga disease, disorder or condition in a mammal that would benefit from FXRmodulation comprising administering a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is atheroscleroticdisease. In some embodiments, is a method of treating a disease,disorder or condition in a mammal that would benefit from FXR modulationcomprising administering a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is atheroscleroticcardiovascular disease. In some embodiments, is a method of treating adisease, disorder or condition in a mammal that would benefit from FXRmodulation comprising administering a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is Syndrome X. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising administeringa compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt or solvate thereof, wherein the disease, disorder or condition in amammal is diabetes mellitus. In some embodiments, is a method oftreating a disease, disorder or condition in a mammal that would benefitfrom FXR modulation comprising administering a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is type II diabetes. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder orcondition in a mammal is insulin insensitivity. In some embodiments, isa method of treating a disease, disorder or condition in a mammal thatwould benefit from FXR modulation comprising administering a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder or condition in a mammal ishyperglycemia. In some embodiments, is a method of treating a disease,disorder or condition in a mammal that would benefit from FXR modulationcomprising administering a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is cholestasis. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising administeringa compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV), or a pharmaceutically acceptablesalt or solvate thereof, wherein the disease, disorder or condition in amammal is obesity.

In some embodiments, is a method of modulating FXR activity comprisingcontacting FXR, or portion thereof, with a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, is an FXR agonist. In someembodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, is an FXR partial agonist.

In some embodiments, the disease, disorder or condition in a mammal thatwould benefit from FXR modulation is selected from nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis and obesity.

Compounds

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇cycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₅ cycloalkyl, optionally substituted, aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In one embodiment is a compound of Formula (I) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (I) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (I) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (I) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (I) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(I) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (I) wherein R⁴ and R⁵form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (I) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (I) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl, R³ is—C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl, R³ is—S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted heteroaryl. In another embodiment is a compound of Formula(I) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substituted aryl.In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (I) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (I) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are methyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (I) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (I) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (I) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (I) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R¹ and R² together with the carbon atoms to whichthey are attached, form an optionally substituted C₂-C₉heterocycloalkylring or an optionally substituted heteroaryl ring. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R¹ and R² together with the carbon atoms to which they areattached, form an optionally substituted C₂-C₉heterocycloalkyl ring. Ina further embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R¹ and R² together with the carbon atoms to whichthey are attached, form an optionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (Ia) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ia) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ia) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ia) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ia) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ia) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ia) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ia) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ia) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ia) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ia) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ia) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ia) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ia) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ia)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ia) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ia)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ia) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ia) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ia) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ia) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ia) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ia) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ia) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ia) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ia) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ia) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ia) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ia) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ia) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ia) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ia) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ia) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ia) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ia) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ia) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ia) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ib), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (Ib) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ib) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ib) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ib) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ib) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ib) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ib) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ib) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ib) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ib) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ib) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ib) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ib) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ib) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ib)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ib) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ib)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ib) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ib) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ib) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ib) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ib) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ib) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ib) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ib) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ib) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ib) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ib) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ib) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ib) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ib) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ib) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ib) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ib) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ib) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ib) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ib) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ic), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (Ic) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ic) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ic) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ic) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ic) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ic) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ic) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ic) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ic) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ic) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ic) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ic) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ic) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ic) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ic)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ic) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ic)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ic) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ic) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ic) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ic) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ic) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ic) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ic) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ic) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ic) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ic) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ic) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ic) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ic) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ic) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ic) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ic) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ic) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ic) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ic) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ic) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ic) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Id), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In another embodiment is a compound of Formula (Id) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Id) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Id) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Id) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Id) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Id) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Id) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Id) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Id) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Id) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Id) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Id) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Id) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Id) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Id) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Id) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Id) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Id) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Id) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Id) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Id)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Id) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Id)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Id) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Id) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Id) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Id) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Id) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Id) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Id) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Id) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Id) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Id) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Id) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Id) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Id) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Id) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Id) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Id) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Id) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Id) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Id) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Id) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Id) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ie), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ie) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ie) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ie) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ie) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ie) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ie) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ie) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ie) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ie) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ie) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ie) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ie) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ie) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ie) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ie)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ie) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ie)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ie) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ie) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ie) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ie) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ie) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ie) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ie) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ie) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ie) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ie) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ie) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ie) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ie) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ie) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ie) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ie) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ie) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ie) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ie) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ie) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ie) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (If), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (If) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (If) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(If) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (If) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (If) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (If) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(If) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (If) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (If) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (If) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(If) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (If) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (If) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (If) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (If) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (If) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (If) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (If) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (If) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (If) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (If)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (If) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (If)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (If) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (If) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(If) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(If) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (If) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (If) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (If) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (If) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(If) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (If) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (If) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (If) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (If) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (If) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (If) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (If) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (If) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (If) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (If) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (If) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (If) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ig), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ig) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ig) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ig) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ig) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ig) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ig) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ig) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ig) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ig) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ig) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ig) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ig) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ig) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ig) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ig)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ig) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ig)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ig) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ig) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ig) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ig) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ig) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ig) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ig) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ig) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ig) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ig) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ig) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ig) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ig) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ig) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ig) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ig) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ig) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ig) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ig) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ig) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ig) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ih), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ih) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ih) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ih) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ih) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ih) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ih) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ih) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ih) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ih) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ih) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ih) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ih) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ih) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ih) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ih)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ih) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ih)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ih) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ih) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ih) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ih) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ih) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ih) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ih) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ih) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ih) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ih) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ih) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ih) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ih) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ih) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ih) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ih) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ih) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ih) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ih) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ih) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ih) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ii), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ii) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ii) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ii) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ii) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ii) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ii) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ii) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ii) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ii) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ii) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ii) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ii) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ii) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ii) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ii)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ii) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ii)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ii) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ii) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ii) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ii) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ii) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ii) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ii) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ii) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ii) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ii) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ii) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ii) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ii) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ii) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ii) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ii) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ii) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ii) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ii) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ii) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ii) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (I) has thestructure of Formula (Ii), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (Ij) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ij) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ij) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (Ij) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (Ij) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (Ij) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(Ij) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (Ij) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Ij) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Ij) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Ij) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (Ij) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (Ij) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (Ij) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ij)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (Ij) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (Ij)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (Ij) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (Ij) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ij) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ij) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ij) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ij) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ij) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (Ij) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Ij) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ij) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ij) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ij) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Ij) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Ij) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (Ij) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Ij) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ij) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ij) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Ij) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ij) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Ij) wherein R⁸ ishydrogen.

In yet another aspect, provided herein is a compound having thestructure of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In one embodiment is a compound of Formula (II) wherein p is 0. Inanother embodiment is a compound of Formula (II) wherein p is 1. Inanother embodiment is a compound of Formula (II) wherein p is 2. Inanother embodiment is a compound of Formula (II) wherein p is 3. Inanother embodiment is a compound of Formula (II) wherein p is 4.

In another embodiment is a compound of Formula (II) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (II) wherein p is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (II) wherein p is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (II)wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (II) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (II) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (II) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (II) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (II) wherein p is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (II) wherein p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (II) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (II)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (II) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (II) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (II) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (II) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (II) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (II) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (II) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (II) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (II) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (II) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (II) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (II) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (II) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(II) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (II) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (II) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (II) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (II) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (II) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (II) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (II) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (II) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R²

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (II) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (II) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (II) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (II) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIa), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIa) wherein p is 0. Inanother embodiment is a compound of Formula (IIa) wherein p is 1. Inanother embodiment is a compound of Formula (IIa) wherein p is 2. Inanother embodiment is a compound of Formula (IIa) wherein p is 3. Inanother embodiment is a compound of Formula (IIa) wherein p is 4.

In another embodiment is a compound of Formula (IIa) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIa) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIa) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIa) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIa) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIa) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIa) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIa) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIa) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIa) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIa)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIa) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIa) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIa) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIa) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIa) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIa) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIa) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIa) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIa) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIa) wherein n is 0. Inanother embodiment is a compound of Formula (IIa) wherein n is 1. Inanother embodiment is a compound of Formula (IIa) wherein n is 2. Inanother embodiment is a compound of Formula (IIa) wherein n is 3.

In another embodiment is a compound of Formula (IIa) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIa)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIa) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIa) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIa)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIa) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIa) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIa) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIa) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIa) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIa) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIa) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIa) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIa) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIa) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIa) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIa) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIa) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIa) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIa) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIa) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIa) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIa) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIa) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIa) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIa) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIa) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIa) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIa) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIa) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIa) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIa) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIa) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIa) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIa) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIa) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIb), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIb) wherein p is 0. Inanother embodiment is a compound of Formula (IIb) wherein p is 1. Inanother embodiment is a compound of Formula (IIb) wherein p is 2. Inanother embodiment is a compound of Formula (IIb) wherein p is 3. Inanother embodiment is a compound of Formula (IIb) wherein p is 4.

In another embodiment is a compound of Formula (IIb) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIb) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIb) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIb) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIb) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIb) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIb) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIb) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIb) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIb) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIb)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIb) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIb) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIb) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIb) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIb) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIb) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIb) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIb) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIb) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIb) wherein n is 0. Inanother embodiment is a compound of Formula (IIb) wherein n is 1. Inanother embodiment is a compound of Formula (IIb) wherein n is 2. Inanother embodiment is a compound of Formula (IIb) wherein n is 3.

In another embodiment is a compound of Formula (IIb) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIb)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIb) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIb) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIb)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIb) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIb) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIb) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIb) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIb) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIb) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIb) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIb) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIb) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIb) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIb) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIb) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIb) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIb) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIb) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIb) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIb) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIb) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIb) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIb) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIb) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIb) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIb) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIb) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIb) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIb) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIb) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIb) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIb) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIb) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIb) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIc), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIc) wherein p is 0. Inanother embodiment is a compound of Formula (IIc) wherein p is 1. Inanother embodiment is a compound of Formula (IIc) wherein p is 2. Inanother embodiment is a compound of Formula (IIc) wherein p is 3. Inanother embodiment is a compound of Formula (IIc) wherein p is 4.

In another embodiment is a compound of Formula (IIc) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIc) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIc) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIc) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIc) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIc) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIc) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIc) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIc) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIc) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIc) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIc) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIc)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIc) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIc) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIc) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIc) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIc) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIc) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIc) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIc) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIc) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIc) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIc) wherein n is 0. Inanother embodiment is a compound of Formula (IIc) wherein n is 1. Inanother embodiment is a compound of Formula (IIc) wherein n is 2. Inanother embodiment is a compound of Formula (IIc) wherein n is 3.

In another embodiment is a compound of Formula (IIc) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIc)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIc) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIc) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIc) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIc)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIc) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIc) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIc) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIc) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIc) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIc) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIc) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIc) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIc) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIc) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIc) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIc) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIc) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIc) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIc) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIc) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIc) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIc) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIc) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIc) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIc) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIc) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIc) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIc) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIc) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIc) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIc) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIc) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIc) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIc) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIc) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIc) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIc) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIc) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIc) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IId), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IId) wherein p is 0. Inanother embodiment is a compound of Formula (IId) wherein p is 1. Inanother embodiment is a compound of Formula (IId) wherein p is 2. Inanother embodiment is a compound of Formula (IId) wherein p is 3. Inanother embodiment is a compound of Formula (IId) wherein p is 4.

In another embodiment is a compound of Formula (IId) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IId) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IId) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IId) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IId) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IId) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IId) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IId) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IId) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IId) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IId) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IId) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IId)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IId) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IId) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IId) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IId) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IId) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IId) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IId) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IId) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IId) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IId) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IId) wherein n is 0. Inanother embodiment is a compound of Formula (IId) wherein n is 1. Inanother embodiment is a compound of Formula (IId) wherein n is 2. Inanother embodiment is a compound of Formula (IId) wherein n is 3.

In another embodiment is a compound of Formula (IId) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IId)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IId) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IId) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IId) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IId)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IId) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IId) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IId) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IId) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IId) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IId) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IId) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IId) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IId) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IId) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IId) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IId) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IId) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IId) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IId) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IId) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IId) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IId) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IId) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IId) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IId) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IId) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IId) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IId) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IId) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IId) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IId) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IId) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IId) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IId) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IId) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IId) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IId) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IId) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IId) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIe), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (IIe) wherein p is 0. Inanother embodiment is a compound of Formula (IIe) wherein p is 1. Inanother embodiment is a compound of Formula (IIe) wherein p is 2. Inanother embodiment is a compound of Formula (IIe) wherein p is 3. Inanother embodiment is a compound of Formula (IIe) wherein p is 4.

In another embodiment is a compound of Formula (IIe) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIe) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIe) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIe) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIe) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIe) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIe) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIe) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIe) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIe) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIe) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIe) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIe)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIe) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIe) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIe) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIe) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIe) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIe) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIe) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIe) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIe) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIe) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIe) wherein n is 0. Inanother embodiment is a compound of Formula (IIe) wherein n is 1. Inanother embodiment is a compound of Formula (IIe) wherein n is 2.

In another embodiment is a compound of Formula (IIe) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIe)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIe) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIe) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIe) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIe)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIe) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIe) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIe) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIe) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIe) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIe) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIe) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIe) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIe) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIe) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIe) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIe) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIe) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIe) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIe) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIe) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIe) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIe) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIe) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIe) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIe) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIe) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIe) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIe) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIe) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIe) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIe) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIe) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIe) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIe) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIe) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIe) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIe) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIe) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIe) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIf), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (IIf) wherein p is 0. Inanother embodiment is a compound of Formula (IIf) wherein p is 1. Inanother embodiment is a compound of Formula (IIf) wherein p is 2. Inanother embodiment is a compound of Formula (IIf) wherein p is 3. Inanother embodiment is a compound of Formula (IIf) wherein p is 4.

In another embodiment is a compound of Formula (IIf) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIf) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIf) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIf) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIf) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIf) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIf) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIf) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIf) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIf) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIf) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIf) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIf)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIf) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIf) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIf) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIf) wherein R³ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIf) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIf) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIf) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIf) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIf) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIf) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIf) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIf) wherein n is 0. Inanother embodiment is a compound of Formula (IIf) wherein n is 1. Inanother embodiment is a compound of Formula (IIf) wherein n is 2. Inanother embodiment is a compound of Formula (IIf) wherein n is 3.

In another embodiment is a compound of Formula (IIf) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIf)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIf) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIf) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIf) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIf)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIf) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIf) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIf) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIf) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIf) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIf) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIf) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIf) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIf) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIf) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIf) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIf) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIf) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIf) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIf) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIf) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIf) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIf) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIf) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁₋C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIf) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIf) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIf) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIf) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIf) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIf) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIf) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIf) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIf) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIf) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIf) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIf) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIf) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIf) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIf) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIf) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIg), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In one embodiment is a compound of Formula (IIg) wherein p is 0. Inanother embodiment is a compound of Formula (IIg) wherein p is 1. Inanother embodiment is a compound of Formula (IIg) wherein p is 2. Inanother embodiment is a compound of Formula (IIg) wherein p is 3. Inanother embodiment is a compound of Formula (IIg) wherein p is 4.

In another embodiment is a compound of Formula (IIg) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIg) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIg) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIg) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIg) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIg) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIg) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIg) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIg) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIg) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIg) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIg) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIg)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIg) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIg) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIg) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIg) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIg) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIg) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIg) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIg) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIg) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIg) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIg) wherein n is 0. Inanother embodiment is a compound of Formula (IIg) wherein n is 1. Inanother embodiment is a compound of Formula (IIg) wherein n is 2.

In another embodiment is a compound of Formula (IIg) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIg)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIg) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIg) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIg) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIg)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIg) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIg) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIg) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIg) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIg) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIg) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIg) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIg) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIg) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIg) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIg) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIg) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIg) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIg) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIg) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIg) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIg) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIg) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIg) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIg) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIg) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIg) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIg) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIg) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIg) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIg) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIg) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIg) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIg) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIg) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIg) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIg) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIg) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIg) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIg) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIh), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIh) wherein p is 0. Inanother embodiment is a compound of Formula (IIh) wherein p is 1. Inanother embodiment is a compound of Formula (IIh) wherein p is 2. Inanother embodiment is a compound of Formula (IIh) wherein p is 3. Inanother embodiment is a compound of Formula (IIh) wherein p is 4.

In another embodiment is a compound of Formula (IIh) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIh) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIh) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIh) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIh) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIh) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIh) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIh) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIh) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIh) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIh) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIh) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIh)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIh) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIh) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIh) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIh) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIh) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIh) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIh) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIh) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIh) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIh) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIh) wherein n is 0. Inanother embodiment is a compound of Formula (IIh) wherein n is 1. Inanother embodiment is a compound of Formula (IIh) wherein n is 2.

In another embodiment is a compound of Formula (IIh) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIh)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIh) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIh) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIh) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIh)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIh) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIh) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIh) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIh) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIh) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIh) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIh) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIh) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIh) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIh) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIh) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIh) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIh) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIh) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIh) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIh) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIh) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIh) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIh) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIh) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIh) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIh) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIh) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIh) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIh) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIh) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIh) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIh) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIh) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIh) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIh) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIh) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIh) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIh) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIh) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIi), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIi) wherein p is 0. Inanother embodiment is a compound of Formula (IIi) wherein p is 1. Inanother embodiment is a compound of Formula (IIi) wherein p is 2. Inanother embodiment is a compound of Formula (IIi) wherein p is 3. Inanother embodiment is a compound of Formula (IIi) wherein p is 4.

In another embodiment is a compound of Formula (IIi) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIi) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIi) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIi) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIi) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIi) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIi) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIi) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIi) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIi) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIi) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIi) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIi)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIi) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIi) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIi) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIi) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIi) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIi) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIi) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIi) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (Ii) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIi) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIi) wherein n is 0. Inanother embodiment is a compound of Formula (IIi) wherein n is 1. Inanother embodiment is a compound of Formula (IIi) wherein n is 2.

In another embodiment is a compound of Formula (IIi) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIi)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIi) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIi) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIi) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIi)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIi) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIi) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIi) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIi) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIi) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIi) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIi) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIi) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIi) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIi) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIi) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIi) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIi) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIi) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIi) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIi) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIi) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIi) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIi) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIi) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIi) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIi) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIi) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIi) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIi) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIi) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIi) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIi) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIi) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIi) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIi) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIi) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIi) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIi) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIi) wherein R⁸ ishydrogen.

In some embodiments provided herein, the compound of Formula (II) hasthe structure of Formula (IIj), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In one embodiment is a compound of Formula (IIj) wherein p is 0. Inanother embodiment is a compound of Formula (IIj) wherein p is 1. Inanother embodiment is a compound of Formula (IIj) wherein p is 2. Inanother embodiment is a compound of Formula (IIj) wherein p is 3. Inanother embodiment is a compound of Formula (IIj) wherein p is 4.

In another embodiment is a compound of Formula (IIj) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IIj) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IIj) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IIj) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIj) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIj) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IIj) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIj) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIj) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IIj) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIj) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIj) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IIj)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIj) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIj) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIj) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIj) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IIj) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIj) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IIj) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIj) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IIj) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IIj) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IIj) wherein n is 0. Inanother embodiment is a compound of Formula (IIj) wherein n is 1. Inanother embodiment is a compound of Formula (IIj) wherein n is 2.

In another embodiment is a compound of Formula (IIj) wherein n is 1 andR¹¹ is halogen. In another embodiment is a compound of Formula (IIj)wherein n is 1 and R¹¹ is F. In another embodiment is a compound ofFormula (IIj) wherein n is 1 and R¹¹ is Cl. In another embodiment is acompound of Formula (IIj) wherein n is 1 and R¹¹ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIj) wherein n is 1 and R¹¹is C₁-C₆alkoxy. In another embodiment is a compound of Formula (IIj)wherein n is 1 and R¹¹ is —OCH₂CH₂OH. In another embodiment is acompound of Formula (IIj) wherein n is 2 and each R¹¹ is independentlyhalogen, C₁-C₆alkyl, or C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IIj) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIj) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIj) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IIj) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIj) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (IIj) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IIj) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IIj) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIj) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IIj) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IIj) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IIj) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IIj) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIj) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIj) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIj) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIj) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IIj) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIj) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIj) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIj) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IIj) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IIj) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IIj) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIj) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IIj) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIj) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IIj) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIj) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIj) wherein R⁸ ishydrogen.

In another aspect, provided herein is a compound having the structure ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring;    -   each R¹⁵ is independently selected from the group consisting of        halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl, —C(O)OR¹², —C(O)N(R¹³)R¹⁴, —OC(O)OR¹²,        —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and —N(R¹³)C(O)N(R¹³)R¹⁴;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   n is 0, 1, 2, or 3    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In one embodiment is a compound of Formula (III) wherein p is 0. Inanother embodiment is a compound of Formula (III) wherein p is 1. Inanother embodiment is a compound of Formula (III) wherein p is 2. Inanother embodiment is a compound of Formula (III) wherein p is 3. Inanother embodiment is a compound of Formula (III) wherein p is 4.

In another embodiment is a compound of Formula (III) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (III) wherein p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (III) wherein p is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(III) wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (III) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (III) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (III) wherein p is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (III) wherein p is 1 and R³¹is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (III)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (III) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (III) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (III) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (III) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (III) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (III) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (III) wherein n is 0. Inanother embodiment is a compound of Formula (III) wherein n is 1. Inanother embodiment is a compound of Formula (III) wherein n is 2. Inanother embodiment is a compound of Formula (III) wherein n is 3.

In another embodiment is a compound of Formula (III) wherein n is 1 andR¹⁵ is halogen. In another embodiment is a compound of Formula (III)wherein n is 1 and R¹⁵ is F. In another embodiment is a compound ofFormula (III) wherein n is 1 and R¹⁵ is Cl. In another embodiment is acompound of Formula (III) wherein n is 1 and R¹⁵ is optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein n is 1 and R¹⁵ is optionally substituted C₁-C₆alkoxy. Inanother embodiment is a compound of Formula (III) wherein n is 1 and R¹⁵is —OCH₂CH₂OH. In another embodiment is a compound of Formula (III)wherein n is 2 and each R¹⁵ is independently selected from the groupconsisting of halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,—C(O)N(R¹³)R¹⁴, —OC(O)OR¹², —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and—N(R¹³)C(O)N(R¹³)R¹⁴. In another embodiment is a compound of Formula(III) wherein n is 2 and each R¹⁵ is independently halogen, optionallysubstituted C₁-C₆alkyl, or optionally substituted C₁-C₆alkoxy.

In another embodiment is a compound of Formula (III) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (III) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (III) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (III) wherein R⁴ and R⁵ are each methyl. In anotherembodiment is a compound of Formula (III) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(III) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (III) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (III) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (III) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (III) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (III) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (III) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (III) wherein R² is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (III) whereinR² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁₋C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (III) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R² is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (III) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (III) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (III) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (III) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (III) wherein R¹ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R⁸ ishydrogen.

In another aspect, provided herein is a compound having the structure ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring;

-   -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring;    -   each R¹⁵ is independently selected from the group consisting of        halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl, —C(O)OR¹², —C(O)N(R¹³)R¹⁴, —OC(O)OR¹²,        —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and —N(R¹³)C(O)N(R¹³)R¹⁴;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₁-C₆alkylamine, optionally substituted        C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl,        aryl, heteroaryl,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   n is 0, 1, 2, or 3    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In one embodiment is a compound of Formula (IV) wherein p is 0. Inanother embodiment is a compound of Formula (IV) wherein p is 1. Inanother embodiment is a compound of Formula (IV) wherein p is 2. Inanother embodiment is a compound of Formula (IV) wherein p is 3. Inanother embodiment is a compound of Formula (IV) wherein p is 4.

In another embodiment is a compound of Formula (IV) wherein p is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IV) wherein p is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein p is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (IV)wherein p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is F, pis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is F, p is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein p is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein p is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IV) wherein p is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (IV) wherein p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is F, pis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, p is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IV)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IV) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IV) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IV) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment is a compound ofFormula (IV) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is

and p is 0.

In another embodiment is a compound of Formula (IV) wherein n is 0. Inanother embodiment is a compound of Formula (IV) wherein n is 1. Inanother embodiment is a compound of Formula (IV) wherein n is 2. Inanother embodiment is a compound of Formula (IV) wherein n is 3.

In another embodiment is a compound of Formula (IV) wherein n is 1 andR¹⁵ is halogen. In another embodiment is a compound of Formula (IV)wherein n is 1 and R¹⁵ is F. In another embodiment is a compound ofFormula (IV) wherein n is 1 and R¹⁵ is Cl. In another embodiment is acompound of Formula (IV) wherein n is 1 and R¹⁵ is optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein n is 1 and R¹⁵ is optionally substituted C₁-C₆alkoxy. Inanother embodiment is a compound of Formula (IV) wherein n is 1 and R¹⁵is —OCH₂CH₂OH. In another embodiment is a compound of Formula (IV)wherein n is 2 and each R¹⁵ is independently selected from the groupconsisting of halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,—C(O)N(R¹³)R¹⁴, —OC(O)OR¹², —OC(O)N(R¹³)R¹⁴, —N(R¹³)C(O)OR¹², and—N(R¹³)C(O)N(R¹³)R¹⁴. In another embodiment is a compound of Formula(IV) wherein n is 2 and each R¹⁵ is independently halogen, optionallysubstituted C₁-C₆alkyl, or optionally substituted C₁-C₆alkoxy.

In another embodiment is a compound of Formula (IV) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IV) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IV) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IV) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (IV) wherein R⁴ and R⁵ form an optionallysubstituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring. In some embodiments is a compound of Formula(IV) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments is a compound of Formula (IV) wherein R⁴ andR⁵ form an optionally substituted C₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (IV) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IV) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IV) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IV) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IV) wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IV) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IV) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IV) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IV) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (IV) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IV) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IV) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R²is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IV) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R²is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IV) wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R¹ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R¹is hydrogen. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IV) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IV) wherein R¹ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (IV) whereinR¹ is optionally substituted C₂-C₆alkenyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IV) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R¹ and R² together with the carbon atoms towhich they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R¹ andR² together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R⁸ isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IV) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IV) wherein R⁸ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IV) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R⁸ ishydrogen.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments is a compound selected from:

of a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments is a compound selected from:

or a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments, the therapeutic agent(s) (e.g. compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II),(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj),(III), or (IV)) is present in the pharmaceutical composition as apharmaceutically acceptable salt. In some embodiments, any compounddescribed above is suitable for any method or composition describedherein.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns. In some embodiments, acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV) is used as a single enantiomer. Insome embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), (Ii), (IIj), (III), or (IV) is used as aracemic mixture.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structurespresented herein, as well as active metabolites of these compoundshaving the same type of activity.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Incertain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV),as set forth herein are included within the scope of the claims. In somecases, some of the herein-described compounds may be a prodrug foranother derivative or active compound.

In specific embodiments, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. In other embodiments, the compounds describedherein exist in unsolvated form.

In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV)described herein include solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol.

In some embodiments, sites on the compounds of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV)disclosed herein are susceptible to various metabolic reactions.Therefore incorporation of appropriate substituents at the places ofmetabolic reactions will reduce, minimize or eliminate the metabolicpathways. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium oran alkyl group.

In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV)disclosed herein are isotopically-labeled, which are identical to thoserecited in the various formulae and structures presented herein, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. In some embodiments, one or more hydrogen atomsare replaced with deuterium. In some embodiments, metabolic sites on thecompounds described herein are deuterated. In some embodiments,substitution with deuterium affords certain therapeutic advantagesresulting from greater metabolic stability, such as, for example,increased in vivo half-life or reduced dosage requirements.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV), are in various forms, including but not limitedto, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, melting points,density, hardness, crystal shape, optical properties, stability, andsolubility. Various factors such as the recrystallization solvent, rateof crystallization, and storage temperature may cause a single crystalform to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (Iiquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following schemes.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which two atoms ofthe alkyl group form a double bond that is not part of an aromaticgroup. Non-limiting examples of an alkenyl group include —CH═CH₂,—C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and —C(CH₃)═CHCH₃. The alkenylmoiety may be branched, straight chain, or cyclic (in which case, itwould also be known as a “cycloalkenyl” group). Alkenyl groups may have2 to 6 carbons.

Alkenyl groups can be substituted or unsubstituted. Depending on thestructure, an alkenyl group can be a monoradical or a diradical (i.e.,an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the twoatoms of the alkyl group form a triple bond. Non-limiting examples of analkynyl group include —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The“R” portion of the alkynyl moiety may be branched, straight chain, orcyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can besubstituted or unsubstituted. Depending on the structure, an alkynylgroup can be a monoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedi-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂C₁, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. In some embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl,heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl,aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂, —OH,—NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In someembodiments, substituted groups are substituted with one or two of thepreceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic, saturated or unsaturatedcarbon atoms, excluding aromatic carbon atoms) includes oxo (═O).

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV), as well as active metabolites of these compounds having the sametype of activity.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of an FXR modulator that, when administered to a mammal inneed, is effective to at least partially ameliorate or to at leastpartially prevent diseases, disorders or conditions described herein.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “FXR modulator” includes FXR agonists, antagonists and tissueselective FXR modulators, as well as other agents that induce theexpression and/or protein levels of FXR in cells.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human. Those skilled in the artrecognize that a therapy which reduces the severity of a pathology inone species of mammal is predictive of the effect of the therapy onanother species of mammal.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions and Methods of Administration of FXRModulators

Administration of FXR modulators as described herein can be in anypharmacological form including a therapeutically effective amount of anFXR modulator alone or in combination with a pharmaceutically acceptablecarrier.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV) described herein, with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Thecompounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV) can be used singly or in combinationwith one or more therapeutic agents as components of mixtures (as incombination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (Ii), (IIj), (III), or (IV) described herein, canbe formulated into any suitable dosage form, including but not limitedto, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries,suspensions, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe FXR modulator and the particular therapeutic effect to be achievedand (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the FXR modulatoractivities disclosed herein in assay preparations of target cells. Exactdosages are determined in conjunction with standard dose-responsestudies. It will be understood that the amount of the compositionactually administered will be determined by a practitioner, in the lightof the relevant circumstances including the condition or conditions tobe treated, the choice of composition to be administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such FXR modulators can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. FXR modulators that exhibit large therapeuticindices are preferred. While FXR modulators that exhibit toxic sideeffects may be used, care should be taken to design a delivery systemthat targets such modulators to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch FXR modulators lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any FXR modulatorused in a method described herein, the therapeutically effective dosecan be estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofFXR modulator that achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the modulation of FXR, or for the treatment of diseasesor conditions that would benefit, at least in part, from modulation ofFXR. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, or pharmaceutically acceptable solvate or hydrate thereof, intherapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.01 mg per day to about 5000 mg per day, in some embodiments,about 1 mg per day to about 1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.001 mg/kg to about 30 mg/kg. In oneembodiment, the daily dosages are from about 0.01 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.1 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.Such dosages may be altered depending on a number of variables, notlimited to the activity of the compound used, the disease or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

EXAMPLES

The following examples are offered for purposes of illustration, and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Example 1: Synthesis of propan-2-yl4-chloro-12-(3,4-dichlorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(8)

Step 1:1-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine (1)

Paraformaldehyde (2.2 g, 72 mmol) and dimethylamine hydrochloride (5.9g, 72 mmol) were added to a stirred solution of5-chloro-1H-pyrrolo[2,3-b]pyridine (10 g, 65.6 mmol) in n-butanol (60mL). The reaction was heated at reflux for 3 h. The solution was allowedto cool to rt and quenched by addition of saturated NaHCO₃ solution. Theresulting mixture was extracted with ethyl acetate (500 mL×3). Theorganic extracts were combined, washed with brine (500 mL), dried overanhydrous sodium sulfate, and concentrated to give compound 1 (13.8 g,100% yield), which was used in the next reaction without purification.LC-MS: 210.21 (M+H), C₁₀H₁₂ClN₃. ¹H NMR (DMSO, 400 MHz) δ 12.33 (br,1H), 10.727 (br, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 4.41 (s,2H), 2.69 (s, 6H).

Step 2:1-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N,N-trimethylmethanaminiumiodide (2)

Iodomethane (10 mL, 164 mmol) was added dropwise to a stirred solutionof compound 1 (13.8 g, 65.6 mmol) in THF (300 mL) at 0° C. The reactionwas then stirred at rt overnight. The resulting precipitate wascollected and dried to give compound 2 (21 g, 91% yield), which was usedin the next reaction without purification. LC-MS: 224.22 (M+),C₁₁H₁₅ClIN₃. ¹H NMR (DMSO, 400 MHz) δ: 12.47 (br, 1H), 8.51-8.46 (m,1H), 8.32 (s, 1H), 7.98-7.94 (m, 1H), 4.69 (s, 2H), 3.13 (s, 3H), 3.06(s, 6H).

Step 3: 2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (3)

Sodium cyanide (6 g, 120 mmol) was added to a stirred solution ofcompound 2 (21 g, 60 mmol) in water (750 mL). The reaction was stirredfor 2 h at 100° C. then cooled. The mixture was extracted with ethylacetate (200 mL×3). The organic extracts were combined, dried overanhydrous sodium sulfate, and concentrated. The residue was purified byflash chromatography (DCM/MeOH, 50/1) give compound 3 (6.5 g, 52% yield)as a white solid. LC-MS: 190.07 (M−H), C₉H6ClN₃. ¹H NMR (DMSO, 400 MHz)δ: 11.98 (br, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 4.06 (s,2H).

Step 4: tert-Butyl5-chloro-3-(cyanomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4)

Boc₂O (7 g, 32.3 mmol) was added to a stirred solution of compound 3(6.5 g, 34 mmol) and DMAP (410 mg, 3.4 mmol) in THF (170 mL). Thereaction was stirred for 10 min at rt. The reaction was quenched byaddition of citric acid (10%). The resulting mixture was extracted withethyl acetate. The organics were combined, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give compound 4 (6 g,60% yield) as white solid. LC-MS: 292.3 (M+H), C₁₄H₁₄ClN₃O₂. ¹H NMR(CDCl₃, 300 MHz) δ: 8.51 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 3.78 (s,2H), 1.69 (s, 9H).

Step 5: tert-Butyl5-chloro-3-(2-cyanopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(5)

A suspension of sodium hydride (1.37 g, 34.2 mmol, 60% in mineral oil)in DMF (40 mL) was cooled to −40° C. under nitrogen. A mixture ofcompound 4 (4.0 g, 13.7 mmol) and iodomethane (2.6 mL, 41.1 mmol) in DMF(40 mL) was added dropwise to the suspension. The reaction was warmed to−10° C. and stirred for 3 h then quenched by addition of saturatedammonium chloride solution. The resulting mixture was extracted withethyl acetate. The organic extracts were combined, washed with brine,dried over anhydrous sodium sulfate and concentrated. The residue wascombined purified by silica gel column chromatography to give compound 5(3.0 g, 68% yield). LC-MS: 320.3 (M+H), C₁₆H₁₈ClN₃O₂. ¹H NMR (CDCl₃, 400MHz) δ: 8.42 (s, 1H), 8.03 (s, 1H), 7.52 (s, 1H), 1.75 (s, 6H), 1.60 (s,9H).

Step 6:2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropanenitrile (6)

To a stirred solution of compound 5 (0.5 g, 1.57 mmol) in EA (4 mL) wasadded 3 N HCl/EA (4 mL). The reaction mixture was stirred at rtovernight then quenched by addition of aqueous NaHCO₃. The mixture wasextracted with EA twice. The organics were combined, washed with brine,dried over anhydrous sodium sulfate and concentrated to give compound 6(0.33 g, 97% yield) as a light yellow oil, which was used in the nextreaction without purification. LC-MS: 218.23 (M−H), C₁₁H₁₀ClN₃. ¹H NMR(CDCl₃, 300 MHz) δ: 12.83 (br, 1H), 10.69 (br, 2H), 8.65 (s, 1H), 8.46(s, 1H), 7.66 (s, 1H), 1.86 (s, 6H).

Step 7:2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpropan-1-amine (7)

LiAlH₄ (120 mg, 3.13 mmol) was added in portions to a stirred solutionof compound 6 (330 mg, 1.57 mmol) in THF (10 mL) at 0° C. The reactionwas then heated at 70° C. and stirred for 5 h. The reaction mixture wasthen allowed to cool to rt and quenched with water. The mixture wasacidified to pH 2-3 with 2 N HCl and washed with ethyl acetate. Thewater phase was basified to pH 8 with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic extracts werecombined, dried over anhydrous sodium sulfate, and concentrated to givecompound 7 (0.22 g, 66% yield), which was used in the next reactionwithout purification. LC-MS: 224.0 (M+H), C₁₁H₁₄ClN₃. ¹H NMR (CDCl₃, 400MHz) (10.27 (br, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.15 (s, 1H), 2.95 (s,2H), 1.39 (s, 6H).

Step 8: Isopropyl 3-chloro-5,5-dimethyl-5,6,7,10-tetrahydropyrido[3′,2′:4,5] pyrrolo[2,3-d]azepine-9-carboxylate (8)

A mixture of compound 7 (160 mg, 0.71 mmol), isopropyl3-bromo-2-oxopropanoate (300 mg, 1.43 mmol), and activated carbon (2 mg)in isopropanol (5 mL) was heated at 120° C. for 1.2 h under microwaveirradiation. Activated carbon was filtered off and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (PE/EA, from 20/1 to 10/1) to give compound 8 (52 mg, 22%yield) as a yellow solid. LC-MS: 334.32 (M+H), C₁₇H₂₀ClN₃O₂. ¹H NMR(CDCl₃, 400 MHz) δ 11.35 (br, 1H), 8.04 (br, 1H), 7.95 (br, 2H),5.20-5.14 (m, 1H), 3.27 (br, 1H), 1.50 (s, 6H), 1.31 (d, J=6.0 Hz, 6H).

Step 9: Propan-2-yl4-chloro-12-(3,4-dichlorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(9)

To a stirred solution of compound 8 (105 mg, 0.31 mmol) and DIPEA (0.55mL, 3.10 mmol) in dichloromethane (5 mL), 3, 4-dichlorobenzoyl chloride(0.65 g, 3.10 mmol) in DCM (2 mL) was added. The reaction mixture wasstirred at rt for 10 mins and it was then diluted with DCM. The mixturewas washed with aqueous NaHCO₃ and brine. The organics were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EA, from 20/1 to 10/1)to afford the title compound (130 mg, 81%) as a yellow solid. LC-MS:508.20 (M+H), C₂₄H₂₂Cl₃N₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ: 11.17 (br, 1H),8.23 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.55 (d, J=8.0Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 5.20-5.14 (m, 1H), 4.06 (br, 1H), 1.57(s, 6H), 1.23 (d, J=6.0 Hz, 6H).

Example 2: Synthesis of propan-2-yl4-chloro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(10)

To a stirred solution of compound 8 (52 mg, 0.15 mmol) and DIPEA (0.13mL, 0.75 mmol) in dichloromethane (4 mL), 3, 4-difluorobenzoyl chloride(0.09 mL, 0.75 mmol) in DCM (1 mL) was added. The reaction mixture wasstirred at rt for 10 mins and it was then diluted with DCM. The mixturewas washed with aqueous NaHCO₃ and brine. The organics were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EA, from 20/1 to 10/1)to afford the title compound (33 mg, 43%). LC-MS: 474.30 (M+H),C₂₄H₂₂ClF₂N₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ 11.10 (br, 1H), 8.23 (s, 1H),8.04 (s, 1H), 7.90 (s, 1H), 7.54-7.49 (m, 1H), 7.38-7.34 (m, 1H),7.29-7.22 (m, 1H), 5.19-5.13 (m, 1H), 4.06 (br, 1H), 1.56 (s, 6H), 1.22(d, J=6.4 Hz, 6H).

Example 3: Synthesis of propan-2-yl4-chloro-12-(4-fluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(11)

To a stirred solution of compound 8 (100 mg, 0.30 mmol) and DIPEA (0.52mL, 3.0 mmol) in dichloromethane (5 mL), 4-fluorobenzoyl chloride (0.48g, 3.0 mmol) in DCM (2 mL) was added. The reaction mixture was stirredat rt for 10 mins and it was then diluted with DCM. The mixture waswashed with aqueous NaHCO₃ and brine. The organics were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EA, from 20/1 to 10/1)to afford the title compound (100 mg, 73%) as a yellow solid. LC-MS:456.41 (M+H), C₂₄H₂₃ClFN₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ 11.20 (br, 1H),8.22 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.65-7.62 (m, 2H), 7.18-7.14(m, 2H), 5.18-5.12 (m, 1H), 4.07 (br, 1H), 1.57 (s, 6H), 1.20 (d, J=6.0Hz, 6H).

Example 4: Synthesis of propan-2-yl5-chloro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(22)

Step 1: 5-Chloro-2-((trimethylsilyl)ethynyl)pyridin-3-amine (12)

Ethynyltrimethylsilane (42.8 g, 0.44 mol) was added dropwise to astirred mixture of 2-bromo-5-chloropyridin-3-amine (45 g, 0.22 mol),Pd(PPh₃)₂Cl₂ (15.5 g, 22 mmol), CuI (4.2 g, 22 mmol), and triethylamine(66 g, 0.66 mol) in THF (400 mL) at 0° C. The reaction mixture wasstirred for 5 h at rt under nitrogen. The mixture was diluted with water(1.2 L) and extracted with ethyl acetate (1 L×3). The organic extractswere combined, washed with brine (300 mL×3), dried over anhydrous sodiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give compound 12 (39 g, 80% yield). LC-MS: 225.01(M+H), C₁₀H₁₃ClN₂Si. ¹H NMR (CDCl₃, 400 MHz) δ: 7.92 (s, 1H), 7.04 (s,1H), 4.36 (br, 2H), 0.29 (s, 9H).

Step 2: 6-Chloro-1H-pyrrolo[3,2-b]pyridine (13)

Sodium hydride (34 g, 0.85 mol, 60% in mineral oil) was added inportions to a solution of compound 12 (38 g, 0.17 mol) in DMF (200 mL)at 0° C. The reaction was stirred for 5 h at rt under nitrogen. Themixture was poured into ice-water (500 mL) and extracted with ethylacetate (500 mL×3). The organic extracts were combined, washed withbrine (200 mL×2), dried over anhydrous sodium sulfate, and concentrated.The residue was purified by silica gel column chromatography to givecompound 13 (20 g, 78% yield). LC-MS: 153.14 (M+H), C₇H₅ClN₂. ¹H NMR(DMSO-d6, 400 MHz) δ 11.48 (br, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.70(m, 1H), 6.59 (m, 1H).

Step 3:1-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine (14)

Paraformaldehyde (3.26 g, 0.11 mol) and dimethylamine hydrochloride(8.85 g, 0.11 mol) were added to a solution of compound 13 (15 g, 98.7mmol) in n-butanol (60 mL). The reaction was refluxed for 2 h. Thesolution was allowed to cool to rt and poured into 15% HCl (100 mL). Thebutanol layer was discarded and the water phase was adjusted to pH13-14with 2M NaOH. The resulting mixture was extracted with ethyl acetate(100 mL×3). The organic extracts were combined, washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated to givecompound 14 (20 g, 97% yield), which was used in the next reactionwithout purification. LC-MS: 210.27 (M+H), C₁₀H₁₂ClN₃.

Step 4:1-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N,N-trimethylmethanaminiumiodide (15)

Iodomethane (67.9 g, 0.48 mol) was added dropwise to a stirred solutionof compound 14 (20 g, 95.7 mmol) in THF (60 mL) at 0° C. The reactionwas stirred for another 2 h at 0° C. The resulting precipitate wascollected and washed with dichloromethane (30 mL) to give compound 15(27 g, 80% yield), which was used in the next reaction withoutpurification.

The compound was confirmed with LC-MS: 224.15 (M−I), C₁H₁₅ClIN₃.

Step 5: 2-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile (16)

Sodium cyanide (8.4 g, 0.17 mol) was added to a stirred mixture ofcompound 15 (30 g, 85.5 mmol) in water (100 mL). The reaction mixturewas stirred at 100° C. for 1 h. The resulting precipitate was collectedand the filtrate was extracted with ethyl acetate (100 mL×3). Theorganic extracts were combined, dried over anhydrous sodium sulfate, andconcentrated. The residue was combined with the collected solid to givecompound 16 (15 g, 92% yield), which was used in the next reactionwithout purification. The compound was confirmed with LC-MS: 192.19(M+H), C₉H6ClN₃.

Step 6: tert-Butyl6-chloro-3-(cyanomethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (17)

Boc₂O (27.4 g, 0.13 mmol) was added to a stirred solution of compound 16(16 g, 83.8 mmol) and DMAP (1.36 g, 8.4 mmol) in THF (100 mL). Thereaction mixture was stirred for another hour at rt. The solvent wasremoved in vacuo and the residue was purified by silica gel columnchromatography to give compound 17 (17 g, 70% yield) as white solid.LC-MS: 292.32 (M+H), C₁₄H₁₄ClN₃O₂. ¹H NMR (CDCl₃, 300 MHz) δ 8.51 (s,1H), 8.45 (s, 1H), 7.90 (s, 1H), 3.92 (s, 2H), 1.70 (s, 9H).

Step 7: tert-Butyl6-chloro-3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(18)

Sodium hydride (11.8 g, 0.29 mol, 60% in mineral oil) was added inportions to a stirred solution of compound 17 (17 g, 58.4 mmol) in DMF(60 mL) at −40° C. (internal temperature was kept between −30° C. and−40° C.). The mixture was stirred for further 10 min at this temperatureand iodomethane (40 g, 0.28 mol) was added. The reaction mixture wasthen stirred for additional hour at −40° C. The reaction was quenchedwith ice water (200 mL) and extracted with ethyl acetate (200 mL×3). Theorganic extracts were combined, washed with brine (100 mL), dried overanhydrous sodium sulfate, and concentrated. The residue was combinedpurified by silica gel column chromatography to give compound 18 (12 g,64% yield). LC-MS: 320.30 (M+H), C₁₆H₁₈ClN₃O₂. ¹H NMR (CDCl₃, 300 MHz) δ8.52 (s, 1H), 8.43 (s, 1H), 7.81 (s, 1H), 1.95 (s, 2H), 1.70 (s, 9H).

Step 8:2-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile (19)

A solution of compound 18 (0.5 g, 1.6 mmol) in 4 N HCl/dioxane (mL) washeated at 80° C. for 3 h. The solvent was removed in vacuo. The residuewas dissolved in water (20 mL) and basified to pH 9 with saturatedsodium bicarbonate solution. The resulting mixture was extracted withethyl acetate (20 mL×3). The organic extracts were combined, washed withbrine (20 mL), dried over anhydrous sodium sulfate, and concentrated togive compound 19 (0.33 g, 96% yield), which was used in the nextreaction without purification. LC-MS: 220.23 (M+H), C₁₁H₁₀ClN₃.

Step 9:2-(6-Chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropan-1-amine (20)

LiAlH₄ (76 mg, 2 mmol) was added in portions to a stirred solution ofcompound 19 (219 mg, 1 mmol) in THF (10 mL) at 0° C. The reaction wasstirred at 70° C. for 2 h. The reaction mixture was allowed to cool tort and quenched with water (0.5 mL). The mixture was acidified to pH 2-3with 2 N HCl and washed with ethyl acetate (5 mL). The aqueous phase wasbasified to pH 8 with saturated sodium bicarbonate solution andextracted with ethyl acetate (5 mL×3). The organic extracts werecombined, dried over anhydrous sodium sulfate, and concentrated to givecompound 20 (0.2 g, 90% yield, containing ˜20% de-chloro product), whichwas used in the next reaction without purification. LC-MS: 224.33 (M+H),C₁₁H₁₄ClN₃.

Step 10: Isopropyl3-chloro-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(21)

A mixture of compound 20 (50 mg, 0.22 mmol), isopropyl3-bromo-2-oxopropanoate (93 mg, 0.45 mmol), and activated carbon (2 mg)in isopropanol (5 mL) was heated at 110° C. for 30 min under microwaveirradiation. Activated carbon was filtered off and the filtrate wasconcentrated. Another batch of microwave irradiation was carried outwith compound 20 (150 mg, 0.67 mmol), isopropyl 3-bromo-2-oxopropanoate(442 mg, 2.7 mmol), and activated carbon (5 mg) for an hour at 110° C.The crude materials of two batches were combined and purified by silicagel column chromatography, then prep-HPLC to give compound 21 (90 mg,30% yield). The compound was confirmed with LC-MS: 334.04 (M+H),C₁₇H₂₀ClN₃O₂.

Step 11: Propan-2-yl5-chloro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(22)

3, 4-Difluorobenzoyl chloride (37 mg, 0.21 mmol) and DIPEA (27 mg, 0.21mmol) were added to a stirred solution of compound 21 (10 mg, 0.03 mmol)in dichloromethane (0.5 mL) at rt and the final reaction mixture wasstirred for 30 min at rt. Another batch of acylation was carried outwith compound 21 (80 mg, 0.24 mmol). The two batches were combined andconcentrated in vacuo. The residue was purified by silica gel columnchromatography and then by prep-HPLC and washed with petroleum/ethylacetate (20:1, 1 mL×3) to afford the title product, compound 22 (25 mg,19% yield). LC-MS: 474.81 (M+H), C₂₄H₂₂ClF₂N₃O₃. ¹H NMR (CDCl₃, 400 MHz)δ: 10.88 (br, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.54-7.49(m, 1H), 7.39-7.36 (m, 1H), 7.29-7.23 (m, 1H), 5.19-5.12 (m, 1H), 4.05(br, 1H), 1.71 (s, 6H), 1.23 (d, J=6.0 Hz, 6H).

Example 5: Synthesis of propan-2-yl5-fluoro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(33)

Step 1: 5-Fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine (23)

Ethynyltrimethylsilane (0.82 mL, 6.3 mmol) was added dropwise to astirred mixture of 2-bromo-5-fluoropyridin-3-amine (1.0 g, 5.23 mmol),Pd(PPh₃)₂Cl₂ (0.18 g, 0.26 mmol) and CuI (50 mg, 0.26 mmol) intriethylamine (15 mL) at 0° C. The reaction was stirred for 4 h at rtunder nitrogen. The mixture was concentrated under reduce pressure. Theresidue was purified by silica gel column chromatography (PE/EA, from20/1 to 10/1) to give compound 23 (0.8 g, 73% yield). LC-MS: 209.16(M+H), C₁₀H₁₃FN₂Si. ¹H NMR (CDCl₃, 400 MHz) δ: 7.83 (s, 1H), 6.75-6.72(m, 1H), 4.40 (br, 2H), 0.28 (s, 9H).

Step 2: 6-Fluoro-1H-pyrrolo[3,2-b]pyridine (24)

t-BuOK (11.3 g, 101 mmol) was added to a stirred solution of compound 23(7.5 g, 33.65 mmol) in DMF (100 mL) at 0° C. The reaction was stirredfor 2 h at rt under nitrogen. The mixture was poured into ice-water (100mL) and extracted with ethyl acetate (200 mL×3). The organic extractswere combined, washed with brine (200 mL×2), dried over anhydrous sodiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography to give compound 24 (3.7 g, 75% yield). LC-MS: 137.11(M+H), C₇H₅FN₂. ¹H NMR (CDCl₃, 400 MHz) δ: 7.85 (s, 1H), 6.75-6.72 (m,1H), 4.41 (br, 2H).

Step 3:1-(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine (25)

Paraformaldehyde (0.24 g, 8.1 mmol) and dimethylamine hydrochloride(0.66 g, 8.1 mmol) were added to a stirred solution of compound 24 (1.0g, 7.35 mmol) in n-butanol (10 mL). The reaction was refluxed for 3 h.The solution was allowed to cool to rt and poured into 15% HCl (100 mL).The butanol layer was discarded and the water phase was adjusted topH13-14 with 2M NaOH. The resulting mixture was extracted with ethylacetate (100 mL×3). The organic extracts were combined, washed withbrine (100 mL), dried over anhydrous sodium sulfate, and concentrated togive compound 25 (1.0 g, 71% yield), which was used in the next reactionwithout purification. LC-MS: 194.02 (M+H), C₁₀H₁₂FN₃. ¹H NMR (CDCl₃, 400MHz) δ: 10.13 (br, 1H), 8.36 (s, 1H), 7.31-7.22 (m, 2H), 3.75 (s, 2H),2.32 (s, 6H).

Step 4:1-(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N,N-trimethylmethanaminiumiodide (26)

Iodomethane (0.81 mL, 13.0 mmol) was added dropwise to a stirredsolution of compound 25 (1.0 g, 5.2 mmol) in THF (20 mL) at 0° C. Thereaction was stirred at rt overnight. The resulting precipitate wascollected and dried to give compound 26 (1.3 g, 76% yield), which wasused in the next reaction without purification. LC-MS: 208.25 (M+),C₁₁H₁₅FIN₃. ¹H NMR (D₂O, 400 MHz) δ: 8.11 (s, 1H), 7.83 (s, 1H),7.55-7.52 (m, 1H), 4.56 (s, 2H), 3.15 (s, 3H), 3.04 (s, 6H).

Step 5: 2-(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile (27)

Sodium cyanide (0.37 g, 7.6 mmol) was added to a stirred solution ofcompound 26 (1.3 g, 3.8 mmol) in water (30 mL). The reaction mixture wasstirred for 2 h at 100° C., then, allowed to cool. The mixture wasextracted with ethyl acetate (50 mL×3). The organic extracts werecombined, dried over anhydrous sodium sulfate, and concentrated to givecompound 27 (0.24 g, 36% yield), which was used in the next reactionwithout purification. LC-MS: 174.04 (M−H), C₉H₆FN₃. ¹H NMR (DMSO, 300MHz) δ: 11.47 (br, 1H), 8.38 (s, 1H), 7.73-7.68 (m, 2H), 4.03 (s, 2H).

Step 6: tert-Butyl6-fluoro-3-(cyanomethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (28)

Boc₂O (0.28 g, 1.3 mmol) was added to a stirred solution of compound 27(0.24 g, 1.37 mmol) and DMAP (17 mg, 0.14 mmol) in THF (10 mL). Themixture was stirred for 10 min at rt. The reaction was quenched byaddition of citric acid (10%). The resulting mixture was extracted withethyl acetate. The organics extracts were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give compound 28 (0.33g, 88% yield) as a white solid. LC-MS: 276.0 (M+H), C₁₄H₁₄FN₃O₂. ¹H NMR¹H NMR (CDCl₃, 300 MHz) δ: 8.45 (s, 1H), 8.16 (br, 1H), 7.90 (s, 1H),3.93 (s, 2H), 1.70 (s, 9H).

Step 7: tert-Butyl6-fluoro-3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(29)

A suspension of sodium hydride (120 mg, 3.0 mmol, 60% in mineral oil) inDMF (10 mL) was cooled to −40° C. under nitrogen. A mixture of compound28 (330 mg, 1.2 mmol) and iodomethane (0.22 mL, 3.6 mmol) in DMF (10 mL)was added dropwise. The mixture was allowed to warm to −10° C. andstirred for 4 h, then quenched by addition of saturated ammoniumchloride solution. The resulting mixture was extracted with ethylacetate. The organic extracts were combined, washed with brine, driedover anhydrous sodium sulfate and concentrated. The residue was combinedpurified by silica gel column chromatography to give compound 29 (0.29g, 80% yield). LC-MS: 304.36 (M+H), C₁₆H₁₈FN₃O₂. ¹H NMR (CDCl₃, 400 MHz)δ: 8.46 (s, 1H), 8.13 (br, 1H), 7.79 (s, 1H), 1.94 (s, 6H), 1.68 (s,9H).

Step 8:2-(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile (30)

To a stirred solution of compound 29 (0.24 g, 0.95 mmol) in EA (3 mL)was added 3 N HCl/EA (3 mL). The reaction was stirred at rt overnightthen concentrated. LCMS showed a mixture of product and startingmaterial. Another portion of HCl/EA (5 mL) was added and the reactionwas stirred at rt for further 5 h then concentrated again. The residuewas slurried in EA (5 mL) for 0.5 h then filtered. The cake was driedunder vacuum to give compound 30 (0.18 g, 93% yield) as a white solid,which was used in the next reaction without purification. LC-MS: 204.04(M+H), C₁₁H₁₀FN₃. ¹H NMR (DMSO, 300 MHz) δ: 11.68 (br, 1H), 8.44 (s,1H), 7.79-7.75 (m, 1H), 7.67 (s, 1H), 1.84 (s, 6H).

Step 9:2-(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropan-1-amine (31)

A solution of compound 30 (0.20 g) in methanol (100 mL) with Raneynickel (0.2 g in water) was hydrogenated in Parr hydrogenator (4 atm) atrt overnight. The solid was filtered off and the filtrate wasconcentrated to afford compound 31 as a light yellow solid (0.20 g,quantitative), which was used in the next reaction without purification.LC-MS: 208.04 (M+H), C₁₁H₁₄FN₃. ¹H NMR (DMSO, 300 MHz) δ 11.45 (br, 1H),8.34 (s, 1H), 7.90 (br, 2H), 7.70-7.66 (m, 1H), 7.47 (s, 1H), 3.27 (s,2H), 1.47 (s, 6H).

Step 10: Isopropyl 3-cfluoro-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(32)

A mixture of compound 31 (80 mg, 0.48 mmol), isopropyl3-bromo-2-oxopropanoate (130 mg, 0.72 mmol), and activated carbon (2 mg)in isopropanol (4 mL) was heated at 110° C. for 2 h under microwaveirradiation. Activated carbon was filtered off and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (PE/EA, 20/1 then DCM/CH₃OH, 20/1), followed byMS-triggered prep-HPLC to give compound 32 (90 mg, 34% yield) as yellowsolid. LC-MS: 318.41 (M+H), C₁₇H₂₀FN₃O₂. ¹H NMR (CDC1 ₃, 300 MHz) δ:11.23 (br, 1H), 8.26 (s, 1H), 77.97 (br, 1H), 7.28 (s, 1H), 5.66 (br,1H), 5.21-5.13 (m, 1H), 3.29 (br, 2H), 1.65 (s, 6H), 1.34 (d, J=6.0 Hz,6H).

Step 11: Propan-2-yl5-fluoro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(33)

3, 4-Difluorobenzoyl chloride a stirred solution of compound 32 (40 mg,0.126 mmol) and DIPEA (0.20 mL, 1.26 mmol) in dichloromethane (4 mL), 3,4-difluorobenzoyl chloride (0.14 mL, 1.26 mmol) in DCM (1 mL) was added.The reaction mixture was stirred for 30 min at rt. Another batch ofacylation reaction was carried out with compound 32 (15 mg, 0.047 mmol).The two batches were combined, washed with saturated NaHCO₃ solution andbrine. The organics were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography to afford a yellow solid, which was slurried in a mixtureof PE/EA (2 mL, 20/1) to give the title compound (25 mg, 31%). LC-MS:458.40 (M+H), C₂₄H₂₂F₃N₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ: 10.86 (br, 1H),8.36 (s, 1H), 8.88 (s, 1H), 7.53-7.48 (m, 1H), 7.39-7.22 (m, 3H),5.18-5.12 (m, 1H), 4.11 (br, 1H), 1.71 (s, 6H), 1.23 (d, J=6.0 Hz, 6H).

Example 6: Synthesis of propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-4-methoxy-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(42)

Step 1:1-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine (34)

Paraformaldehyde (0.22 g, 7.43 mmol) and dimethylamine hydrochloride(0.61 g, 7.43 mmol) were added to a stirred solution of5-methoxy-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.76 mmol) in n-butanol (10mL). The reaction was refluxed for 3 h. The solution was allowed to coolto rt and quenched by addition of saturated NaHCO₃ solution. Theresulting mixture was extracted with ethyl acetate (100 mL×3). Theorganic extracts were combined, washed with brine (100 mL), dried overanhydrous sodium sulfate, and concentrated to give compound 34 (1.22 g,88% yield), which was used in the next reaction without purification.LC-MS: 206.24 (M+H), C₁₁H₁₅N₃O. ¹H NMR (CDCl₃, 300 MHz) δ: 8.73 (br,1H), 7.52 (s, 1H), 7.25 (s, 1H), 6.63-6.56 (m, 1H), 4.00 (s, 3H), 3.75(s, 2H), 2.35 (s, 6H).

Step 2:1-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N,N-trimethylmethanaminiumiodide (35)

Iodomethane (0.93 mL, 14.9 mmol) was added dropwise to a stirredsolution of compound 34 (1.22 g, 5.95 mmol) in THF (30 mL) at 0° C. Thereaction was stirred at rt overnight. The resulting precipitate wascollected and dried to give compound 35 (1.4 g, 70% yield), which wasused in the next reaction without purification. LC-MS: 347.0 (M+H),C₁₂H₁₈IN₃O. ¹H NMR (D₂O, 400 MHz) δ: 7.78 (br, 1H), 7.67 (br, 1H), 6.67(br, 1H), 4.54 (s, 2H), 3.86 (s, 3H), 3.11 (m, 9H).

Step 3: 2-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile (36)

Sodium cyanide (0.40 g, 8.06 mmol) was added to a stirred solution ofcompound 2 (1.4 g, 4.03 mmol) in water (40 mL). The reaction was stirredfor 2 h at 100° C. then cooled. The mixture was extracted with ethylacetate (50 mL×3). The organic extracts were combined, dried overanhydrous sodium sulfate, and concentrated. The residue was purified byflash chromatography (PE/EA, 5/1) give compound 3(0.45 g, 60% yield) asa white solid. LC-MS: 188.22 (M+H), C₁₀H9N₃O. ¹H NMR (CDCl₃, 400 MHz) δ:8.14 (br, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 6.65 (s, 1H), 3.99 (s, 3H),3.91 (d, 2H).

Step 4: tert-Butyl5-methoxy-3-(cyanomethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (37)

Boc₂O (0.52 g, 2.4 mmol) was added to a stirred solution of compound 36(0.45 g, 2.4 mmol) and DMAP (29 mg, 0.24 mmol) in THF (10 mL). Thereaction was stirred for 10 min at rt. The reaction was quenched byaddition of citric acid (10%). The resulting mixture was extracted withethyl acetate. The organics were combined, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give compound 37 (0.55 g, 80% yield) aswhite solid. LC-MS: 288.41 (M+H), C₁₅H₁₇N₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ:8.14 (br, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 6.66-6.64 (m, 1H), 3.99 (s,3H), 3.91 (s, 2H).

Step 5: tert-Butyl5-methoxy-3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(38)

A suspension of sodium hydride (191 mg, 4.8 mmol, 60% in mineral oil) inDMF (10 mL) was allowed to cool to −40° C. under nitrogen. A mixture ofcompound 37 (550 mg, 1.9 mmol) and iodomethane (0.35 mL, 5.7 mmol) inDMF (10 mL) was added dropwise. The reaction mixture was allowed to warmto −10° C. and stirred for 4 h then quenched by addition of saturatedammonium chloride solution. The resulting mixture was extracted withethyl acetate. The organic extracts were combined, washed with brine,dried over anhydrous sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography to give compound 38 (0.43g, 71% yield). LC-MS: 316.40 (M+H), C₁₇H₂₁N₃O₃. ¹H NMR (CDCl₃, 400 MHz)δ 8.11 (br, 1H), 7.55 (m, 1H), 7.29 (m, 1H), 6.72-6.70 (m, 1H), 3.98 (s,3H), 1.96 (s, 6H), 1.66 (s, 6H).

Step 6:2-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile (39)

To a stirred solution of compound 38 (0.43 g, 1.36 mmol) in EA (2 mL)was added 3 N HCl/EA (10 mL). The reaction was stirred at rt for 2 hthen quenched by addition of aqueous NaHCO₃. The mixture was extractedwith EA twice. The organics were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated to give compound 39 (0.28 g,95% yield) as a light yellow oil, which was used in the next reactionwithout purification. LC-MS: 215.96 (M+H), C₁₂H₁₃N₃O. ¹H NMR (CDCl₃, 400MHz) δ 8.10 (br, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 6.62 (d,J=8.8 Hz, 1H), 3.99 (s, 3H), 1.96 (s, 6H).

Step 7:2-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropan-1-amine (40)

A stirred solution of compound 39 (0.28 g) in methanol (100 mL) withRaney nickel (0.2 g in water) was hydrogenated in Parr hydrogenator (4atm) at rt overnight then filtered. The filtrate was concentrated toafford compound 40 as a light yellow solid (0.28 g, quantitative), whichwas used in the next reaction without purification. LC-MS: 220.29 (M+H),C₁₂H₁₇N₃O. ¹H NMR (CDCl₃, 400 MHz) δ 10.87 (br, 1H), 7.64-7.61 (m, 1H),7.17 (s, 1H), 6.49 (s, 1H), 3.87 (s, 3H), 2.89 (s, 2H), 1.36 (s, 6H).

Step 8: Isopropyl2-methoxy-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(41)

A mixture of compound 40 (330 mg, 1.51 mmol), isopropyl3-bromo-2-oxopropanoate (472 mg, 2.27 mmol), and activated carbon (2 mg)in isopropanol (20 mL) was heated at 100° C. for 1 h under microwaveirradiation. Activated carbon was filtered off and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography, followed by MS-triggered prep-HPLC to give compound 41(10 mg, 34% yield) as a yellow solid. LC-MS: 330.38 (M+H), C₁₈H₂₃N₃O₃.¹H NMR (CDCl₃, 400 MHz) δ 11.87 (br, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.37(d, J=8.0 Hz, 1H), 6.37 (br, 1H), 5.11-5.04 (m, 1H), 3.90 (s, 3H), 3.30(br, 2H), 1.57 (br, 6H), 1.26 (d, J=6.0 Hz, 6H).

Step 9: Propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-4-methoxy-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(42)

To a stirred solution of compound 41 (47 mg, 0.143 mmol) and DIPEA (0.25mL, 1.43 mmol) in dichloromethane (4 mL), 3, 4-difluorobenzoyl chloride(0.08 mL, 0.714 mmol) in DCM (1 mL) was added. The reaction was stirredfor 30 min at rt, then diluted with DCM. The mixture was washed withaqueous NaHCO₃ and brine. The organics were dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography to afford a yellow solid, which was furtherpurified by preparative TLC to give the title compound (25 mg, 37%).LC-MS: 470.40 (M+H), C₂₅H₂₅F₂N₃O₄. ¹H NMR (CDCl₃, 400 MHz) δ 10.67 (br,1H), 7.81 (s, 1H), 7.57-7.49 (m, 2H), 7.39-7.36 (m, 1H), 7.27-7.21 (m,1H), 6.60 (d, J=6.0 Hz, 8.4H), 5.17-5.11 (m, 1H), 4.00 (br, 4H), 1.71(s, 6H), 1.23 (d, J=6.4 Hz, 6H).

Example 7: Synthesis of propan-2-yl12-(4-fluorobenzoyl)-14,14-dimethyl-4-methoxy-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(43)

To a stirred solution of compound 41 (56 mg, 0.17 mmol) and DIPEA (0.30mL, 1.70 mmol) in dichloromethane (4 mL), 4-fluorobenzoyl chloride (135mg, 0.85 mmol) in DCM (2 mL) was added. The reaction was stirred for 30min at rt, then diluted with DCM. The mixture was washed with aqueousNaHCO₃ and brine. The organics were dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate, from 100/1 to 50/1 then30/1) to afford the title compound (30 mg, 39%) as a yellow solid.LC-MS: 452.44 (M+H), C₂₅H₂₆FN₃O₄. ¹H NMR (CDCl₃, 400 MHz) δ 10.78 (br,1H), 7.87 (s, 1H), 7.66-7.62 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.15 (t,J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.02 (br, 4H),1.73 (s, 6H), 1.20 (d, J=6.0 Hz, 6H).

Example 8: Synthesis of propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(55)

Step 1: N,N-Dimethyl-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)methanamine (44)

To a solution of 1,4-azaindole (8.7 g, 1.0 eq.) in n-butanol (100 mL)was added formaldehyde (6.6 g. 37% in water, 1.1 eq.) and dimethylaminehydrochloride salt (6.6 g, 1.1 eq.). The resulting mixture was heated atreflux for 3 h. The mixture was cooled and the solvent was removed invacuo. The mixture was diluted with 100 mL ethyl acetate, washed withsaturated NaHCO₃, water and brine, dried over Na₂SO₄ and concentrated invacuo to provide compound 44 (13 g) which was used without furtherpurification.

Step 2: 2-(1H-Pyrrolo[3,2-b]pyridin-3-yl)acetonitrile (45)

To a solution of compound 44 (13 g, 1.0 eq.) in THF (100 mL) was addeddropwise dimethyl sulfate (9.3 g, 1.0 eq.). The resulting mixture washeated at reflux for 30 minutes. The solvent was removed, and theresidue was dissolved in 80 mL water. To the mixture was added KCN (5.3g, 1.1 eq.) and the mixture was refluxed for 3 h. The reaction wascooled to room temperature and extracted from ethyl acetate (3×40 mL).The combined organic layers were concentrated in vacuo to affordcompound 45 (8.3 g) which was used without purification.

Step 3: tert-Butyl3-(2-cyanopropan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (46)

To a solution of compound 45 (8.3 g, 1.0 eq.) in CH₂Cl₂(50 mL) was addeddi-tert-butyl dicarbonate (12.7 g, 1.1 eq.), DMAP (100 mg), and triethylamine (8.1 g, 1.5 eq.). The reaction mixture was stirred at roomtemperature for 2.5 h. The mixture was washed with NH₄Cl, and brine toafford n-Boc protected intermediate (13.5 g). To a solution ofintermediate (13.5 g) and CH₃I (22.5 g, 3.0 eq) in dry THF (100 mL) at−78° C. under N₂ was added LiHMDS (158 mL, 1M in THF, 3.0 eq.) dropwiseover 30 minutes. The resulting mixture was stirred at −78° C. for 20minutes then gradually warmed to 0° C. over 2 h. The reaction wasquenched by saturated NH₄Cl, and then extracted from ethyl acetate(2×150 mL). The organic phase was dried over Na₂SO₄ and concentrated invacuo to provide compound 46 (16.7 g) which was used without furtherpurification.

Step 4:2-Methyl-2-(1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)propanenitrile(47)

To a solution of compound 46 (16.7 g, 1.0 eq) in MeOH (100 mL) was addedK₂CO₃ (40 g, 5.0 eq). The mixture was heated at 60° C. for 1 hr. Theinorganic salt was removed by filtration and the filtrate was dilutedwith 250 mL ethyl acetate, washed with water and brine and concentratedto provide intermediate (10.8 g). To a solution of the intermediate(10.8 g, 1.0 eq) in dry THF (100 mL) at 0° C. was added NaH (3.5 g, 60%,1.5 eq.). The reaction mixture was stirred at 0° C. for 30 minutes andthen benzenesulfonyl chloride (11.4 g, 1.1 eq.) in THF (20 mL) was addeddropwise. The resulting mixture was stirred at 0° C. for 1 h. Thereaction was quenched with ice-water and extracted from ethyl acetate(3×125 mL). The combined organic layers were concentrated in vacuo andthe residue was purified by column chromatography to provide compound 47(7.3 g).

Step 5:2-(2-Iodo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(48)

LDA (45 mL, 1M in THF, 2.0 eq.) was added dropwise to a solution ofcompound 47 (7.3 g, 1.0 eq.) in dry THF (50 mL) at −78° C. under N₂. Themixture was stirred at −78° C. for 30 minutes. I₂ (11.4 g, 2.0 eq.) wasadded to the reaction mixture. The resulting mixture was stirred at −78°C. for 5 minutes then warmed to 0° C. in one hour. The reaction wasquenched by saturated NH₄Cl, washed with 10% Na₂S₂O₅ (30 mL), and brine.The organic phase was dried over Na₂SO₄ and concentrated in vacuo toprovide compound 48 (10.1 g) which was used without furtherpurification.

Step 6: 2-(2-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(49)

To a solution of compound 48 (7.9 g, 1.0 eq.) in THF (10 mL), was addedTBAF (88 mL, 1M in THF, 5.0 eq.). The resulting mixture was stirred atroom temperature for 1 h. The solvent was removed in vacuo. The residuewas dissolved in 100 mL ethyl acetate, washed with saturated NH₄Cl,water and brine. The solvent was concentrated in vacuo to providecompound 49 (5.4 g) which was used without further purification.

Step 7:2-(2-iodo-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(50)

To a solution of compound 49 (5.4 g, 1.0 eq) in dry THF (50 mL), wasadded NaH (2.2 g, 60%, 3.0 eq.) at 0° C. under N₂. The mixture wasstirred at room temperature for 30 minutes, and then p-methoxybenzylchloride (3.3 g, 1.2 eq.) was added dropwise at room temperature. Theresulting mixture was stirred at room temperature for 2 h. The reactionwas quenched with saturated NH₄Cl, washed with water and brine. Thecrude mixture was purified by column chromatography to afford compound50 (5.2 g, 69.5%).

Step 8: Isopropyl2-(3-(2-cyanopropan-2-yl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)acetate(51)

To a solution of compound 50 (1.7 g, 1.0 eq.) in dry THF (50 mL), wasadded Pd(P(tBu)₃)₂ (1.7 g). The mixture was flushed with nitrogen for 5minutes. A solution of (2-isopropoxy-2-oxoethyl) zinc bromide in THF (21mL, ˜0.3M, 1.6 eq.) was added dropwise under N₂. The resulting mixturewas stirred in an oil bath, temperature starting from room temperatureto 70° C. within 10 minutes, and then the reaction was heated at 70° C.for 1 h. The reaction mixture was cooled to room temperature andquenched with 60 mL saturated NH₄Cl. The crude mixture was purified bycolumn chromatography to provide compound 51 (1.5 g, 93.4%).

Step 9: Isopropyl2-(3-(1-(tert-butoxycarbonylamino)-2-methylpropan-2-yl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)acetate(52)

To a solution of compound 51 (1.5 g, 1.0 eq.) in THF (20 mL) and iPrOH(30 mL), was added Boc anhydride (1.6 g, 2.0 eq.), 8 mL Ra—Ni in water,and a few drops of saturated NH₄OH. The resulting mixture washydrogenated at H₂ 40 psi for 5 h. The catalyst was carefully removed byfiltration. The solvent was concentrated in vacuo and the residue waspurified by column chromatography to give compound 52 (1.6 g, 84%).

Step 10: Isopropyl2-(3-(1-(tert-butoxycarbonylamino)-2-methylpropan-2-yl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-3-(dimethylamino)acrylate(53)

A solution of compound 52 (1.6 g) in1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (8 mL) was flushedwith nitrogen and then heated at 115° C. in a sealed-tube for 4 h. Themixture was cooled to room temperature, diluted with 100 mL CH₂Cl₂,washed with water and brine. The crude mixture was purified by columnchromatography to give compound 53 (1.52 g, 85%).

Step 11: Isopropyl10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(54)

To a solution of compound 53 (1.0 g) in TFA (8 mL) was heated at 90° C.for 2 h. The TFA was removed in vacuo. The residue was dissolved in 100mL CH₂Cl₂, washed with saturated NaHCO₃, and brine. The crude mixturewas purified by column chromatography to provide compound 54 (0.42 g,76%).

Step 12: Propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(55)

To a solution of compound 54 (40 mg, 1.0 eq) and DIEA (52 mg, 3.0 eq)CH₂Cl₂ (3 mL) was added 3,4-difluorobenzoyl chloride (59 mg, 2.5 eq).The resulting mixture was stirred at room temperature for 2 h. Themixture was washed with saturated NaHCO₃ and brine. The crude mixturewas purified by column chromatography to provide compound 55 (42 mg,yield 71%). LC-MS: 440.4 (M+H).

Example 9: Synthesis of eth-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(56)

The title compound 56 was prepared using a similar procedure as outlinedin Example 8. LC-MS: 426.1 (M+H).

Example 10: Synthesis of propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(57)

The title compound 57 was prepared using a similar procedure as outlinedin Example 8. LC-MS: 440.1 (M+H).

Example 11: Synthesis of eth-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(58)

The title compound 58 was prepared using a similar procedure as outlinedin Example 8. LC-MS: 440.1 (M+H).

Example 12: Synthesis of propan-2-yl4-fluoro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(59)

The title compound 59 was prepared using a similar procedure as outlinedin Example 2. LC-MS: 440.1 (M+H).

Example 13: Synthesis of propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-5-(2-hydroxyethoxy)-4-chloro-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(72)

Step 1: 6-Fluoro-1H-pyrrolo[3,2-b]pyridine N-oxide (60)

To a stirred solution of compound 24 (1.2 g, 8.8 mol, 1.0 eq.) in DCM(100 mL), was added mCPBA (2.3 g, 13.2 mmol, 1.5 eq.) at roomtemperature. After stirring at room temperature overnight, the reactionwas cooled at 0° C. for 1 h, and then filtered to collect the solid. Thesolid was washed with diethyl ether, and then dried under high vacuumgive compound 60 (1.3 g, 8.5 mmol, 97%) as a solid, which is usedwithout further purification.

Step 2: Methyl 5-chloro-6-fluoro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(61)

To a stirred suspension of compound 60 (1.3 g, 8.5 mmol, 1.0 eq.) andhexamethyldisilazane (1.5 g, 9.4 mmol, 1.1 eq.) in dry THF (80 mL), wasadded methyl chloroformate (2.4 g, 25.5 mmol, 3 eq.). The reaction wasstirred at room temperature for 1 h, and then at 85° C. for 20 hr. Thereaction was quenched with ice/water, and extracted with EtOAc. Theorganic solution was dried over Na₂SO₄, and concentrated to givecompound 61 (1.6 g, 7.0 mmol, 82%) as yellow solid, which is usedwithout further purification.

Step 3: 5-Chloro-6-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine(62)

To a stirred solution of compound 61 (1.6 g, 7.0 mmol, 1.0 eq.) in MeOH,was added MeONa (1.5 g, 21 mmol, 3 eq.) at 0° C. After stirring at 0° C.for 15 min, MeOH was removed under vacuum. The residue was suspended inwater, the pH was adjusted to neutral, and the mixture was extractedwith EtOAc (2×). The organic solution was dried over Na₂SO₄ andconcentrated to dryness to give 1.1 g yellow solid. The solid was addedto a mixture of K₂CO₃ and PMB-Cl in MeCN (50 mL). The reaction washeated at reflux for 4 h and then cooled to room temperature. Themixture was filtered and the filtrate was concentrated. The residue wasdissolved in EtOAc, and washed with water and brine. The organic phasewas concentrated. The residue was purified by silica gel columnchromatography to give compound 62 (1.3 g, 4.5 mmol, 65%) as a whitesolid.

Step 4:6-(2-(Allyloxy)ethoxy)-5-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine(63)

To a solution of 2-allyloxyethanol (0.55 g, 5.4 mmol, 1.2 eq.) in dryDMSO (10 mL), was added NaH (217 mg, 5.4 mmol, 1.2 eq.). After stirringat room temperature for 30 min, a solution of compound 62 in DMSO (1.5mL) was dropped in. The reaction was heated to 80° C. and stirredovernight. The reaction was quenched with water, and extracted withEtOAc/hexane (8/2). The organic phase was washed with water, dried overNa₂SO₄, and concentrated. The residue was purified by silica gel columnchromatography to give compound 63 (1.4 g, 3.7 mmol, 83%) as a whitesolid.

Step 5: 2-(5-Chloro-1H-pyrrolo[3,2-b]pyridin-6-yloxy)ethanol (64)

A mixture of compound 63 (1.4 g, 3.7 mmol, 1.0 eq.) and anisole (1.14 g,11.1 mmol, 3 eq.) in 20 mL TFA was stirred at 130° C. for 48 hrs. TheTFA was removed under high vacuum. The residue was dissolved in DCM, andwashed carefully with saturated NaHCO₃ solution twice. The organicsolution was dried over Na₂SO₄, and concentrated. The residue waspurified with silica gel column chromatography to give compound 64 (630mg, 3.0 mmol, 77%) as a yellow solid.

Step 6:2-(5-Chloro-3-((dimethylamino)methyl)-1H-pyrrolo[3,2-b]pyridin-6-yloxy)ethanol(65)

To a stirred solution of compound 64 (630 mg, 2.97 mmol, 1.0 eq.) inn-BuOH (10 mL), was added 37% formaldehyde in water (2.6 mL, 3.3 mmol,1.1 eq.) and dimethylamine hydrochloride (280 mg, 3.4 mmol, 1.15 eq.).The reaction mixture was heated at reflux for 3 h. After cooling down,the reaction was poured into 1N HCl (80 mL). The butanol layer wasdiscarded and the water phase was adjusted to pH 13-14 with 2M NaOH. Theresulting mixture was extracted with EtOAc. The combined organicsolution was washed with brine, dried over Na₂SO₄, and concentrated togive compound 65 (490 mg, 61%), which was used in the next reactionwithout purification.

Step 7:2-(5-Chloro-6-(2-hydroxyethoxy)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile(66)

To a stirred solution of compound 65 (490 mg, 1.83 mmol, 1.0 eq.) in dryTHF (15 mL), was added dimethyl sulfate (253 mg, 2.0 mmol, 1.1 eq.)dropwise at 0° C. The mixture was heated at reflux for 1 h and cooleddown. The solvent was decanted and the glue like precipitate wascollected and washed with hexane. The residue was dissolved in 20 mLwater and KCN (155 mg, 2.38 mmol, 1.3 eq.) was added. The reaction washeated at reflux for 1.5 h, then allowed to cool. The reaction mixturewas extracted with EtOAc (30 mL×3). The combined organic phase was driedover Na₂SO₄, and concentrated to give compound 66 (460 mg, 99%), whichwas used in the next reaction without purification.

Step 8: tert-Butyl5-chloro-3-(cyanomethyl)-6-(2-hydroxyethoxy)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(67)

To a stirred solution of compound 66 (460 mg, 1.8 mmol, 1.0 eq.) andDMAP (22 mg, 0.18 mmol, 0.1 eq.) in dry THF (15 mL), was added Boc₂O(864 mg, 4.0 mmol, 2.2 eq.). The mixture was stirred at room temperaturefor 30 min, and then diluted with EtOAc (40 mL). The mixture was washedwith 1N HCl, saturate NaHCO₃, and water. The organic phase was driedover Na₂SO₄, and concentrated. The residue was purified with silica gelcolumn chromatography to give compound 67 (380 mg, 47%) as a whitesolid.

Step 9: tert-butyl5-chloro-3-(2-cyanopropan-2-yl)-6-(2-hydroxyethoxy)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(68)

To a stirred solution of compound 67 (380 mg, 0.84 mmol, 1.0 eq.) andiodomethane (360 mg, 2.5 mmol, 3 eq.) in dry THF (5 mL), was added 1MLiHMDS in THF (2.5 mL, 3 eq.) dropwise at −78° C. After stirring at −78°C. for 30 min, the reaction was quenched with water, and extracted withEtOAc. The organic phase was washed with water and brine, dried overNa₂SO₄, and concentrated. The residue was purified with silica gelcolumn chromatography to give compound 68 (250 mg, 63%) as a whitesolid.

Step 10:2-(5-Chloro-6-(2-hydroxyethoxy)-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(69)

To a stirred solution of compound 68 (250 mg, 0.52 mmol, 1.0 eq.) inMeOH (5 mL), was added K₂CO₃ (215 mg, 1.56 mmol, 3 eq.). After stirringat 60° C. for 2 h, the reaction was allowed to cool down, and the solidwas filtered off. The solution was concentrated. The residue wasdissolved in EtOAc, washed with water and brine, dried over Na₂SO₄. Thesolution was concentrated to dryness to give compound 69 (150 mg, 100%)as a white solid.

Step 11:2-(3-(1-Amino-2-methylpropan-2-yl)-5-chloro-1H-pyrrolo[3,2-b]pyridin-6-yloxy)ethanol(70)

To solution of compound 69 (150 mg, 0.52 mmol, 1 eq.) with raney nickel(0.1 g in water) was hydrogenated in Parr hydrogenator (60 psi) at roomtemperature overnight. The solid was filtered off and the filtrate wasconcentrated to afford compound 70 (110 mg, 75%), which was used in thenext reaction without purification.

Step 12: Isopropyl3-(2-hydroxyethoxy)-2-chloro-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(71)

A mixture of compound 70 (110 mg, 0.39 mmol, 1.0 eq.), isopropyl3-bromo-2-oxopropanoate (97 mg, 0.47 mmol, 1.2 eq.), and activatedcarbon (3 mg) in isopropanol (3 mL) was stirred at 110° C. for 2 h undermicrowave irradiation. Activated carbon was filtered off and thefiltrate was concentrated. The residue was purified with silica gelcolumn chromatography to give compound 71 (22.5 mg, 15%) as a whitesolid.

Step 13: Propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-5-(2-hydroxyethoxy)-4-chloro-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(72)

To a solution of compound 71 (22.5 mg, 0.06 mmol, 1.0 eq.) and DIPEA (15mg, 0.12 mmol, 2 eq.) in dichloromethane (2 mL), was added3,4-difluorobenzoyl chloride (12.3 mg, 0.07 mmol, 1.1 eq.) in DCM (1mL). The reaction mixture was stirred for 30 min at room temperature,then washed with saturated NaHCO₃ solution and brine. The organic phasewas dried over Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography to give compound 72 (20 mg, 64%) as a yellowsolid. LC-MS: 534.4 (M+H).

Example 14: Synthesis of propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-4-(2-hydroxyethoxy)-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(84)

Step 1: 2-(2-(Allyloxy)ethoxy)-3-chloro-5-nitropyridine (73)

To a solution of 2-allyloxyethanol (5.8 g, 57 mmol, 1.1 eq.) in dry THF(10 mL), was added NaH (1.37 g, 57 mmol, 1.1 eq.). After stirring atroom temperature for 30 min, the solution was dropped into a solution of2, 3-dichloro-5-nitropyridine (10 g, 52 mmol, 1 eq.) in THF (10 mL) at−20° C. The reaction was stirred for 1 hr. at room temperature, quenchedwith water (50 mL), and extracted with EtOAc. The organic phase waswashed with water, dried over Na₂SO₄, and concentrated to give compound73 (13 g, 97%) as a brown oil.

Step 2: 6-(2-(Allyloxy)ethoxy)-5-chloropyridin-3-amine (74)

To a solution of SnCl₂-2H₂O (6 g, 26 mmol, 2 eq.) in EtOH (40 mL) wasadded compound 73 (3.5 g, 13.5 mmol, 1.0 eq.). The reaction was heatedto reflux. SnCl₂-2H₂O (3 g, 13 mmol, 1 eq.) was added to the reactionevery 30 min until a total 5 eq. of SnCl₂-2H₂O was added. After heatingat reflux overnight, the solvent was removed under vacuum. Water wasadded to the residue. The pH was adjusted to 13-14 with 4N NaOHsolution, and the mixture was extracted with EtOAc. The organic phasewas washed with water, dried over Na₂SO₄, and concentrated. The residuewas purified by silica gel column chromatography (hexane/EtOAc) to givecompound 74 (750 mg, 24%) as a yellow oil.

Step 3: 6-(2-(Allyloxy)ethoxy)-2-bromo-5-chloropyridin-3-amine (75)

To a solution of compound 74 (750 mg, 3.2 mmol, 1 eq.) in acetic acid(10 mL), was added bromine (1.0 g, 6.4 mmol, 2 eq.). The mixture wasstirred at 100° C. for 6 h. Excess Br₂ and AcOH was removed under highvacuum to give compound 75 (780 mg, 77%).

Step 4:6-(2-(Allyloxy)ethoxy)-5-chloro-2-((trimethylsilyl)ethynyl)pyridin-3-amine(76)

To a stirred mixture of compound 75 (780 mg, 2.5 mmol, 1 eq.),Pd(PPh₃)₂Cl₂ (183 mg, 0.26 mmol, 0.1 eq.), and CuI (50 mg, 0.26 mmol,0.1 eq.) in trimethylamine (20 ml), was added ethynyltrimethylsilane(301 mg, 3.1 mmol, 1.2 eq.) at 0° C. The reaction was stirred for 3 hrat room temperature under nitrogen. LCMS indicated the starting materialhas been consumed and two new products were formed. The solid wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane/DCM) to give compound 76 (620 mg, 77%) as a yellow oil.

Step 5: 5-(2-(Allyloxy)ethoxy)-6-chloro-1H-pyrrolo[3,2-b]pyridine (77)

To a solution of compound 76 (620 mg, 1.9 mol, 1.0 eq.) in dry DMF (20mL), was added NaH (185 mg, 7.6 mmol, 4 eq.) at 0° C. After stirring atroom temperature for 5 hr, the reaction was poured into 50 mL ice/water,and extracted with EtOAc/hexane (9/1, 40 mL×2). The organic phase waswashed with water, brine, dried with Na₂SO₄, and concentrated todryness. The residue was purified with silica gel column chromatography(hexane/EtOAc) to give compound 77 (210 mg, 44%) as a brown solid.

Step 6:2-(5-(2-(Allyloxy)ethoxy)-6-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetonitrile(78)

To a solution of compound 77 (210 mg, 0.83 mmol, 1.0 eq.) in n-BuOH (4mL), was added 37% formaldehyde in water (0.8 mL, 1 mmol, 1.2 eq.) anddimethylamine hydrochloride (82 mg, 1 mmol, 1.2 eq.). The reaction washeated at reflux for 1 h. After cooling down, the reaction was pouredinto 1N HCl (80 mL). The butanol layer was discarded and the water phasewas adjusted to pH 13-14 with 2M NaOH. The resulting mixture wasextracted with EtOAc. The combined organic solution was washed withbrine, dried over Na₂SO₄, and concentrated. The residue was dissolved inTHF (6 mL), and dimethyl sulfate (126 mg, 1 mmol, 1.2 eq.) was addeddropwise at 0° C. The mixture was heated at reflux for 1 h andconcentrated. The residue was dissolved in H₂O/THF (5/1, 12 mL) and KCN(82 mg, 1.25 mmol, 1.5 eq.) was added. The reaction was heated at refluxfor 1 h, then allowed to cool down. The reaction was extracted withEtOAc (20 mL×3). The combined organic phase was dried over Na₂SO₄, andconcentrated to give compound 78 (270 mg), which was used in the nextreaction without purification.

Step 7: tert-Butyl5-(2-(allyloxy)ethoxy)-6-chloro-3-(cyanomethyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(79)

To a solution of compound 78 (270 mg, 0.93 mmol, 1.0 eq.) and DMAP (11mg, 0.09 mmol, 0.1 eq.) in dry THF (5 mL), was added Boc₂O (222 mg, 1.0mmol, 1.1 eq.). The mixture was stirred at room temperature for 1.5 hr.,and then diluted with EtOAc (20 mL). The mixture was washed with 1N HCl,saturate NaHCO₃, and water. The organic phase was dried over Na₂SO₄, andconcentrated to give compound 79 (390 mg), which was used in the nextreaction without purification.

Step 8:2-(5-(2-(Allyloxy)ethoxy)-6-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(80)

To a solution of compound 79 (390 mg, 0.99 mmol, 1.0 eq.) andiodomethane (355 mg, 2.5 mmol, 2.5 eq.) in dry THF (4 mL), was added 1MLiHMDS in THF (2.5 mL, 2.5 eq.) dropwise at −78° C. After stirring at−78° C. for 30 min, the reaction was quenched with water, and extractedwith EtOAc. The organic phase was washed with water and brine, driedover Na₂SO₄, and concentrated. The residue and K₂CO₃ (420 mg, 3 mmol, 3eq.) was dissolved in MeOH (5 mL). After stirring at room temperaturefor 30 min, the solid was filtered out and the filtrate wasconcentrated. The residue was dissolved in EtOAc, washed with water andbrine, dried over Na₂SO₄, and concentrated. The residue was purifiedwith silica gel column chromatography (hexane/EtOAc) to give compound 80(150 mg, 56% from compound 77) as a white solid.

Step 9:2-(6-Chloro-5-(2-hydroxyethoxy)-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-methylpropanenitrile(81)

To a solution of RhCl₃—H₂O (30 mg, 0.14 mmol, 0.3 eq.) in EtOH (5 mL),was added compound 80 (150 mg, 0.47 mmol, 1.0 eq.). The reaction mixturewas stirred at room temperature for 2 h. and concentrated. The residuewas purified with silica gel column chromatography (DCM/THF) to givecompound 81 (110 mg, 84%) as a yellow oil.

Step 10:2-(3-(1-Amino-2-methylpropan-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yloxy)ethanol(82)

A solution of compound 81 (110 mg, 0.39 mmol, 1 eq.) with raney nickel(0.1 g in water) was hydrogenated in Parr hydrogenator (60 psi) at roomtemperature overnight. The solid was filtered off and the filtrate wasconcentrated to afford compound 82 (90 mg, 92% yield), which was used inthe next reaction without purification.

Step 11: Isopropyl2-(2-hydroxyethoxy)-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxylate(83)

A mixture of compound 82 (90 mg, 0.36 mmol, 1.0 eq.), isopropyl3-bromo-2-oxopropanoate (85 mg, 0.4 mmol, 1.1 eq.), and activated carbon(3 mg) in isopropanol (3 mL) was stirred at 110° C. for 1 h undermicrowave irradiation. Activated carbon was filtered off and thefiltrate was concentrated. The residue was purified with silica gelcolumn chromatography to give compound 83 (44 mg, 34%) as a yellowsolid.

Step 12: Propan-2-yl12-(3,4-difluorobenzoyl)-14,14-dimethyl-4-(2-hydroxyethoxy)-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(84)

To a solution of compound 83 (44 mg, 0.12 mmol, 1.0 eq.) and DIPEA (24mg, 0.18 mmol, 1.5 eq.) in dichloromethane (4 mL), 3,4-difluorobenzoylchloride (19.4 mg, 0.11 mmol, 0.9 eq.) in DCM (1 mL) was added. Thereaction mixture was stirred for 30 min at room temperature, then washedwith saturated NaHCO₃ solution and brine. The organic phase was driedover Na₂SO₄, and concentrated. The residue was purified with silica gelcolumn chromatography (DCM/EtOAc) to give compound 84 (30 mg, 50%) as ayellow solid. LC-MS: 500.5 (M+H).

Example 15: Synthesis of3-chloro-8-(3,4-difluorobenzoyl)-N-isopropyl-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxamide(85)

To a solution of isopropyl amine (70 mg, 1.10 mol) in toluene, trimethylaluminium [0.4 mL (2 M solution in toluene), 0.90 mol] was added at 0°C. After 15 minutes, compound 22 (110 mg, 0.23 mol) was added andreaction mixture was heated at 110° C. in a seal tube for 16 h. Thereaction was quenched with ice water and extracted with ethyl acetate.The combined ethyl acetate layers were washed with water and brine,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified on silica gel using 30% ethyl acetate in hexane toafford compound 85 (40 mg, 51%) as a yellow solid. LC-MS: 473.1.

Example 16: Synthesis of propan-2-yl4-chloro-12-(4-(2-morpholinoethoxy)benzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(89)

To a solution of methyl 4-hydroxybenzoate (68.1 g, 1.0 eq.) inacetonitrile (1.3 L) was added N-(2-chloroethyl) morpholine HCl salt(99.9 g, 1.2 eq.) and Cs₂CO₃ (291.7 g, 2.0 eq.). The resulting mixturewas stirred and heated at reflux (80° C. oil bath) overnight. Thereaction mixture was cooled to room temperature and the inorganic solidwas filtered off. The solvent was evaporated. The oily residue wasdissolved in EtOAc/hexane mixture (3:1, 500 mL) and washed with water(500 mL). The aqueous layer was re-extracted more with EtOAc/hexane(3:1, 2×100 mL). The combined organic extracts were evaporated in vacuoto give compound 86 (126.1 g) as pale-yellow oil which was used withoutpurification.

A suspension of compound 86 (126.1 g) in 6N HCl (880 mL) was heated atreflux (oil bath at 135° C.) overnight. The reaction mixture wasconcentrated in vacuo to remove most water then cooled at 0° C. Theresulted precipitate was filtered, washed with cold 2N HCl (2×100 mL) togive a white solid. The solid was dried in high vacuum to give compound87 HCl salt (112.9 g, 82%).

A suspension of compound 87 HCl salt (112.8 g) in SOCl₂ (450 mL) washeated at 90° C. for 12 h. The excess SOCl₂ was removed in vacuo to −225mL and the product was precipitated with heptane (560 mL) to provide awhite solid. The solid was filtered, washed with heptane and dried onhigh vacuo to afford compound 88 HCl salt (116 g, 98%).

Compound 89 was prepared from compound 21 and compound 88 usingconditions as described in Example 4, step 11. LC-MS: 567.

Example 17: Synthesis of3-chloro-8-(4-(2-morpholinoethoxy)benzoyl)-N-isopropyl-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxamide(90)

Compound 90 was prepared from compound 89 using conditions as describedin Example 15. LC-MS: 566.4.

Example 18: Synthesis of propan-2-yl12-(4-(2-morpholinoethoxy)benzoyl)-14,14-dimethyl-4-(methoxy)-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(91)

Compound 91 was prepared from compound 41 and compound 88 usingconditions as described in Example 6, step 9. LC-MS: 563.5 (M+H).

Example 19: Synthesis of propan-2-yl5-chloro-4-methoxy-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(101)

Compound 101 was prepared using conditions outlined above and asdescribed in Example 4. LC-MS: 504.4 (M+H).

Example 20: Synthesis of12-(3,4-difluorobenzoyl)-14,14-dimethyl-N-(propan-2-yl)-6,8,12-triazatricyclo[7.5.0.0²′7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxamide(102)

Compound 92 is prepared from compound 57 using conditions described inExample 15.

Example 21: FXR Agonist Transactivation Assay

For the transactivation assay, cells were transiently transfected with100 ng of reporter vector and 10 ng of expression plasmid. Fortynanograms of pGL4.74 was used as internal control for transfectionefficiency. The pGEM vector was added to normalize the amounts of DNAtransfected in each assay (2 μg). All transfections were performed usingFuGENE HD (Roche, Mannheim, Germany) according to the manufacturer'sprotocol. Twenty-four hours after transfection, cells were stimulatedwith increasing concentrations of the test compounds for further 18 h.Control cultures receive vehicle (0.1% DMSO) alone. Luciferase valueswere normalized with Renilla reniformis luciferase units, fortransfection efficiency. Data are shown below in Table 1.

TABLE 1 Compound EC50 (μM) 9 B 10 A 11 B 22 A 33 A 42 A 43 A 55 A 56 A57 A 58 A 59 A 72 B 84 A 85 A 89 A 90 NT 91 A 101 A A, EC₅₀ < 1 μM; B,EC₅₀ = 1-10 μM; NT = not tested

Example 22: Phase 1 Study to Evaluate Safety of a Compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II),(IIa), (IIb), (IIc), (IId), (Ie), (IIf), (IIg), (IIh), (IIi), (IIj),(III), or (IV) in Subjects With Non-Alcoholic Steatohepatitis (NASH) andAdvanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi),(IIj), (III), or (IV) when administered orally to subjects withbiopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of a compound of        Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),        (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf),        (IIg), (IIh), (IIi), (IIj), (III), or (IV);    -   The effects of 2 dose levels (25 mg and 50 mg) of a compound of        Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),        (Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf),        (IIg), (IIh), (IIi), (IIj), (III), or (IV) on insulin resistance        and glucose homeostasis; and    -   Effects of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),        (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),        (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV)        on hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function and inflammation.

Patients:

Eligible subjects will be men and women 18 years to 75 years of age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

The primary objective of this study is to characterize the safety, whichincludes the tolerability and dose-limiting toxicity (DLT), for acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), (IIi), (IIj), (III), or (IV) when administered intravenously tosubjects with biopsy-proven NASH with advanced liver fibrosis.Specifically, this measure will be assessed by number of subjectsexperiencing treatment emergent adverse events indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to characterize the first-dose PK        profile of compound of Formula (I), (Ia), (Ib), (Ic), (Id),        (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (IIc),        (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or (IV).        The PK profile is assessed by the AUC (area under the plasma        concentration versus time curve) and Cmax (peak plasma        concentration) of a compound of Formula (I), (Ia), (Ib), (Ic),        (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb),        (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III),        or (IV).    -   A secondary objective for the study is to characterize the PK        profile and serum level accumulation of a compound of Formula        (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),        (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh),        (IIi), (IIj), (III), or (IV) following administration of daily        oral doses beginning 3 days after the first dose.    -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

Arms Assigned Interventions Active Comparator: Cohort 1 Drug: Compoundof Formula Patient receives dose of compound of (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIb), (If), (Ig), (Ih), (Ii), (Ij), (II),(IIa), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIi), (IIj), (III), or (IV) (IIh), (IIi), (IIj),(III), or (IV) or Drug: Placebo placebo Active Comparator: Cohort 2Drug: Compound of Formula Patient receives dose of compound of (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb), (If), (Ig), (Ih),(Ii), (Ij), (II), (IIa), (IIc), (IId), (IIe), (IIf), (IIg), (IIh),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIi), (IIj), (III), or (IV)(IIh), (IIi), (IIj), (III), or (IV) or Drug: Placebo Placebo ActiveComparator: Cohort 3 Drug: Compound of Formula Patient receives dose ofcompound of (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIb),(If), (Ig), (Ih), (Ii), (Ij), (II), (IIa), (IIc), (IId), (IIe), (IIf),(IIg), (IIh), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIi), (IIj),(III), or (IV) (IIh), (IIi), (IIj), (III), or (IV) or Drug: Placeboplacebo

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of a compoundof Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii),(Ij), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh),(IIi), (IIj), (III), or (IV), in subjects with biopsy-proven NASH withadvanced fibrosis. This is a dose escalation design comprised of 3sequential cohorts to evaluate the safety of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II), (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (III), or(IV) when administered orally once a day for 7 weeks. Each cohort willconsist of 8 subjects, 6 randomized to receive a compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (II),(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj),(III), or (IV) and 2 randomized to receive placebo. Based on data safetymonitoring board (DSMB) and FDA review, 2 additional cohorts may beimplemented, consisting of 8 subjects.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

1.-73. (canceled)
 74. A compound having the structure of Formula (IIa),or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein: R¹ is selected from the group consisting of hydrogen,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,optionally substituted C₂-C₆alkynyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R² is selected from the group consistingof —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring; R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl; or R⁴and R⁵ together with the carbon atom to which they are attached, form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring; R⁶ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and—C(O)N(R²⁷)R²⁸; R⁷ is selected from the group consisting of hydrogen,halogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionallysubstituted C₂-C₆alkynyl; R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); each R¹¹ is independently selected fromthe group consisting of halogen, —CN, amino, alkylamino, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and —C(O)N(R¹³)R¹⁴;each R¹² is independently selected from the group consisting of hydrogenand C₁-C₆alkyl; each R¹³ and R¹⁴ are each independently selected fromthe group consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring; R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R²⁷ and R²⁸ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl); orR²⁷ and R²⁸ together with the nitrogen atom to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring; R³⁰ ishalogen,

each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl; eachR³² and R³³ are each independently selected from the group consisting ofhydrogen, halogen, and C₁-C₆alkyl; R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, and optionallysubstituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with thenitrogen atom to which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring; n is 0, 1, 2, or 3 p is 0, 1, 2, 3, or 4; ris 0, 1, 2, 3, or 4; and t is 2, 3, or
 4. 75. The compound of claim 74,or a pharmaceutically acceptable salt or solvate thereof wherein R² is—C(O)OR²⁵.
 76. The compound of claim 74, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R⁴ and R⁵ are eachindependently optionally substituted C₁-C₆alkyl.
 77. The compound ofclaim 74, or a pharmaceutically acceptable salt or solvate thereof,wherein n is 1 and R¹¹ is halogen.
 78. The compound of claim 74, or apharmaceutically acceptable salt or solvate thereof, wherein R⁴ and R⁵are each optionally substituted C₁-C₆alkyl, R⁶ and R⁷ are each hydrogen,and R² is —C(O)OR²⁵.
 79. The compound of claim 74, or a pharmaceuticallyacceptable salt or solvate thereof, wherein p is 1 and wherein each R³⁰and R³¹ is independently a halogen.
 80. The compound of claim 74,wherein the pharmaceutically acceptable salt is hydrochloride.
 81. Acompound according to Formula (IIa) of claim 74 having the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 82. A compoundof claim 74, having the structure:

or pharmaceutically acceptable salt or solvate thereof.
 83. Apharmaceutical composition comprising a pharmaceutically acceptablediluent, excipient or binder, and a compound of claim 74; or apharmaceutically acceptable salt or solvate thereof.
 84. A method oftreating a disease, disorder or condition in a mammal that would benefitfrom farnesoid X receptor (FXR) modulation comprising administering tothe mammal a compound, or a pharmaceutically acceptable salt or solvatethereof, according to claim
 74. 85. A method of modulating FXR activitycomprising contacting FXR, or portion thereof, with a compound, or apharmaceutically acceptable salt or solvate thereof, according to claim74.
 86. The method of claim 85, wherein the disease, disorder orcondition in a mammal is selected from nonalcoholic steatohepatitis(NASH), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis and obesity.
 87. The method of claim 86,wherein the disease or disorder is nonalcoholic steatohepatitis (NASH).88. A compound having the structure:

or pharmaceutically acceptable salt or solvate thereof.
 89. Apharmaceutical composition comprising a pharmaceutically acceptablediluent, excipient or binder, and a compound of claim 88; or apharmaceutically acceptable salt or solvate thereof.
 90. A compoundhaving the structure:

or pharmaceutically acceptable salt or solvate thereof.
 91. Apharmaceutical composition comprising a pharmaceutically acceptablediluent, excipient or binder, and a compound of claim 90; or apharmaceutically acceptable salt or solvate thereof.